U.S. patent application number 12/664788 was filed with the patent office on 2010-10-14 for substituted bicyclic heteroaryl compounds for the treatment of cardiovascular disease.
Invention is credited to Hartmut Beck, Eva-Maria Becker, Mario Jeske, Raimund Kast, Thomas Lampe, Joachim Schuhmacher, Friederike Stoll.
Application Number | 20100261736 12/664788 |
Document ID | / |
Family ID | 39791691 |
Filed Date | 2010-10-14 |
United States Patent
Application |
20100261736 |
Kind Code |
A1 |
Lampe; Thomas ; et
al. |
October 14, 2010 |
SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS FOR THE TREATMENT OF
CARDIOVASCULAR DISEASE
Abstract
The present application relates to novel substituted bicyclic
heteroaryl compounds, to processes for their preparation, to their
use for the treatment and/or prophylaxis of diseases and to their
use for preparing medicaments for the treatment and/or prophylaxis
of diseases, in particular for the treatment and/or prophylaxis of
cardiovascular diseases.
Inventors: |
Lampe; Thomas; (Dusseldorf,
DE) ; Kast; Raimund; (Wuppertal, DE) ; Beck;
Hartmut; (Koln, DE) ; Stoll; Friederike;
(Dusseldorf, DE) ; Becker; Eva-Maria; (Wuppertal,
DE) ; Jeske; Mario; (Solingen, DE) ;
Schuhmacher; Joachim; (Wuppertal, DE) |
Correspondence
Address: |
Barbara A. Shimei;Director, Patents & Licensing
Bayer HealthCare LLC - Pharmaceuticals, 555 White Plains Road, Third Floor
Tarrytown
NY
10591
US
|
Family ID: |
39791691 |
Appl. No.: |
12/664788 |
Filed: |
June 3, 2008 |
PCT Filed: |
June 3, 2008 |
PCT NO: |
PCT/EP08/04408 |
371 Date: |
June 14, 2010 |
Current U.S.
Class: |
514/260.1 ;
514/265.1; 514/302; 514/469; 544/278; 544/280; 546/116;
549/469 |
Current CPC
Class: |
A61P 7/02 20180101; C07D
487/04 20130101; C07D 307/80 20130101; A61P 9/12 20180101; A61P
9/00 20180101; A61P 9/10 20180101; C07D 491/048 20130101; C07D
495/04 20130101 |
Class at
Publication: |
514/260.1 ;
544/278; 514/265.1; 544/280; 549/469; 514/469; 546/116;
514/302 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 495/04 20060101 C07D495/04; A61P 9/12 20060101
A61P009/12; A61P 7/02 20060101 A61P007/02; C07D 487/04 20060101
C07D487/04; C07D 307/80 20060101 C07D307/80; A61K 31/343 20060101
A61K031/343; C07D 491/048 20060101 C07D491/048; A61K 31/4355
20060101 A61K031/4355 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 16, 2007 |
DE |
10 2007 027 800.6 |
Claims
1. A compound of the formula (I) ##STR00118## in which B, D and E
each represent CH or N, G represents NH, O or S, with the proviso
that G does not represent O if at the same time B and E represent N
and D represents CH, and G does not represent NH or S if at the
same time B, D and E represent CH, A represents O or N--R.sup.3 in
which R.sup.3 represents hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.4-C.sub.7)-cycloalkenyl, M
represents a group of the formula ##STR00119## in which #
represents the point of attachment to the group A and ## represents
the point of attachment to the group Z, R.sup.4 represents hydrogen
or (C.sub.1-C.sub.4)-alkyl which may be substituted by hydroxyl or
amino, L.sup.1 represents (C.sub.1-C.sub.7)-alkanediyl or
(C.sub.2-C.sub.7)-alkenediyl which may be mono- or disubstituted by
fluorine, or represents a group of the formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the group Z, L.sup.1A represents
(C.sub.1-C.sub.5)-alkanediyl which may be mono- or disubstituted by
identical or different substituents from the group consisting of
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, L.sup.1B
represents a bond or (C.sub.1-C.sub.3)-alkanediyl which may be
mono- or disubstituted by fluorine, and V represents O or
N--R.sup.5 in which R.sup.5 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, L.sup.2
represents a bond or (C.sub.1-C.sub.4)-alkanediyl, L.sup.3
represents (C.sub.1-C.sub.4)-alkanediyl which may be mono- or
disubstituted by fluorine and in which a methylene group may be
replaced by O or N--R.sup.6 in which R.sup.6 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, or
represents (C.sub.2-C.sub.4)-alkenediyl, and Q represents
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.4-C.sub.7)-cycloalkenyl,
phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered
heteroaryl, each of which may be substituted by up to two identical
or different radicals selected from the group consisting of
fluorine, chlorine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl,
hydroxyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, amino,
mono-(C.sub.1-C.sub.4)-alkylamino and
di-(C.sub.1-C.sub.4)-alkylamino, where (C.sub.1-C.sub.4)-alkyl for
its part may be substituted by hydroxyl, (C.sub.1-C.sub.4)-alkoxy,
amino, mono- or di-(C.sub.1-C.sub.4)-alkylamino, Z represents a
group of the formula ##STR00120## in which ### represents the point
of attachment to the group L.sup.1 or L.sup.3 and R.sup.7
represents hydrogen or (C.sub.1-C.sub.4)-alkyl, and R.sup.1 and
R.sup.2 are identical or different and independently of one another
represent (C.sub.3-C.sub.7)-cyclo-alkyl,
(C.sub.4-C.sub.7)-cycloalkenyl, phenyl, 5- to 7-membered
heterocyclyl or 5- or 6-membered hetero-aryl each of which may be
mono- to trisubstituted by identical or different radicals selected
from the group consisting of halogen, cyano, nitro,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.4)-alkynyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.4-C.sub.7)-cycloalkenyl, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)-alkylthio,
(C.sub.1-C.sub.6)-acyl, amino, mono-(C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.1-C.sub.6)-alkylamino and (C.sub.1-C.sub.6)-acylamino,
where (C.sub.1-C.sub.6)-alkyl and (C.sub.1-C.sub.6)-alkoxy for
their part may each be substituted by cyano, hydroxyl,
(C.sub.1-C.sub.4)-alkoxy, (C.sub.1-C.sub.4)-alkylthio, amino, mono-
or di-(C.sub.1-C.sub.4)-alkylamino, or R.sup.1 and/or R.sup.2
represent phenyl in which two radicals attached to adjacent ring
carbon atoms together form a group of the formula
--O--CH.sub.2--O--, --O--CHF--O--, --O--CF.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O-- or --O--CF.sub.2--CF.sub.2--O--, or a
salt thereof.
2. The compound of the formula (I) as claimed in claim 1 in which
the bicyclic ring system ##STR00121## represents a heteroaryl group
of the formula ##STR00122## in which represents the point of
attachment to the radical R.sup.1, ** represents the point of
attachment to the radical R.sup.2 and *** represents the point of
attachment to the group -A-M-Z, B, D and E each represent CH or N,
with the proviso that B does not represent N if at the same time D
represents CH and E represents N, and G represents NH or S, A
represents O or N--R.sup.3 in which R.sup.3 represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or cyclopropyl, M represents a group of the
formula ##STR00123## in which # represents the point of attachment
to the group A and ## represents the point of attachment to the
group Z, R.sup.4 represents hydrogen or (C.sub.1-C.sub.3)-alkyl
which may be substituted by hydroxyl or amino, L.sup.1 represents
(C.sub.3-C.sub.7)-alkanediyl or (C.sub.3-C.sub.7)-alkenediyl which
may be mono- or disubstituted by fluorine, or a group of the
formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the group Z, L.sup.1A represents
(C.sub.1-C.sub.3)-alkanediyl which may be mono- or disubstituted by
identical or different substituents from the group consisting of
methyl and ethyl, L.sup.1B represents (C.sub.1-C.sub.3)-alkanediyl
which may be mono- or disubstituted by fluorine, and V represents O
or N--R.sup.5 in which R.sup.5 represents hydrogen,
(C.sub.1-C.sub.3)-alkyl or cyclopropyl, L.sup.2 represents a bond
or (C.sub.1-C.sub.3)-alkanediyl, L.sup.3 represents
(C.sub.1-C.sub.3)-alkanediyl which may be mono- or disubstituted by
fluorine, (C.sub.2-C.sub.3)-alkenediyl or a group of the formula
--W--CR.sup.8R.sup.9-- , --W--CH.sub.2--CR.sup.8R.sup.9-- or
--CH.sub.2--W--CR.sup.8R.sup.9-- in which represents the point of
attachment to the ring Q, represents the point of attachment to the
group Z, W represents O or N--R.sup.6 in which R.sup.6 represents
hydrogen, (C.sub.1-C.sub.3)-alkyl or cyclopropyl, and R.sup.8 and
R.sup.9 independently of one another represent hydrogen or
fluorine, and Q represents (C.sub.4-C.sub.6)-cycloalkyl,
(C.sub.4-C.sub.6)-cycloalkenyl, phenyl or 5- or 6-membered
heterocyclyl, each of which may be up substituted by up to two
identical or different radicals selected from the group consisting
of fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl, trifluoromethyl,
hydroxyl, methoxy, ethoxy, trifluoromethoxy, amino, methylamino,
ethylamino, dimethylamino and diethylamino, Z represents a group of
the formula ##STR00124## in which ### represents the point of
attachment to the group L.sup.1 or L.sup.3 and R.sup.7 represents
hydrogen, methyl or ethyl, and R.sup.1 and R.sup.2 are identical or
different and independently of one another represent
(C.sub.4-C.sub.6)-cyclo-alkenyl, phenyl or 5- or 6-membered
heteroaryl, each of which may be mono- or disubstituted by
identical or different radicals selected from the group consisting
of fluorine, chlorine, cyano, (C.sub.1-C.sub.5)-alkyl,
(C.sub.2-C.sub.5)-alkenyl, (C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.4-C.sub.6)-cycloalkenyl, (C.sub.1-C.sub.4)-alkoxy,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.4)-alkylthio,
(C.sub.1-C.sub.5)-acyl, amino, mono-(C.sub.1-C.sub.4)-alkyl-amino,
di-(C.sub.1-C.sub.4)-alkylamino and (C.sub.1-C.sub.4)-acylamino, or
R.sup.1 and/or R.sup.2 represent phenyl in which two radicals
attached to adjacent ring carbon atoms together form a group of the
formula --O--CH.sub.2--O--, --O--CHF--O-- or
--O--CF.sub.2--O--.
3. The compound of the formula (I) as claimed in claim 1 in which
the bicyclic ring system ##STR00125## represents a heteroaryl group
of the formula ##STR00126## in which represents the point of
attachment to the radical R.sup.1, ** represents the point of
attachment to the radical R.sup.2 and *** represents the point of
attachment to the group -A-M-Z, A represents O or NH, M represents
a group of the formula ##STR00127## in which # represents the point
of attachment to the group A and ## represents the point of
attachment to the group Z, R.sup.4 represents hydrogen, methyl or
ethyl, L.sup.1 represents (C.sub.3-C.sub.7)-alkanediyl,
(C.sub.3-C.sub.7)-alkenediyl or a group of the formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the group Z, L.sup.1A represents
(C.sub.1-C.sub.3)-alkanediyl which may be mono- or disubstituted by
methyl, L.sup.1B represents (C.sub.1-C.sub.3)-alkanediyl and V
represents O or N--CH.sub.3, L.sup.2 represents a bond, methylene,
ethane-1,1-diyl or ethane-1,2-diyl, L.sup.3 represents
(C.sub.1-C.sub.3)-alkanediyl or a group of the formula
--W--CH.sub.2-- or --W--CH.sub.2--CH.sub.2-- in which represents
the point of attachment to the ring Q, represents the point of
attachment to the group Z and W represents O or N--R.sup.6 in which
R.sup.6 represents hydrogen or (C.sub.1-C.sub.3)-alkyl, and Q
represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
morpholinyl or phenyl, each of which may be substituted by up to
two identical or different radicals selected from the group
consisting of fluorine, methyl, ethyl, trifluoromethyl, hydroxyl,
methoxy and ethoxy, Z represents a group of the formula
##STR00128## in which ### represents the point of attachment to the
group L.sup.1 or L.sup.3, and R.sup.1 and R.sup.2 are identical or
different and independently of one another represent
cyclopenten-1-yl, cyclohexen-1-yl, phenyl, thienyl or pyridyl, each
of which may be mono- or disubstituted by identical or different
radicals selected from the group consisting of fluorine, chlorine,
cyano, (C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.1-C.sub.4)-alkoxy, trifluoromethyl and trifluoromethoxy.
4. The compound as claimed in claim 1, in which B, D, and E each
represent CH, G represents O, A represents O or NH, M represents a
group of the formula ##STR00129## in which # represents the point
of attachment to the group A and ## represents the point of
attachment to the carboxylic acid grouping, R.sup.4 represents
hydrogen or methyl, L.sup.1 represents butane-1,4-diyl,
pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid-
. in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the carboxylic acid grouping, L.sup.1A represents
methylene or ethane-1,2-diyl which may be mono- or disubstituted by
methyl, and L.sup.1B represents methylene or ethane-1,2-diyl,
L.sup.2 represents a bond or methylene, L.sup.3 represents
methylene, ethane-1,2-diyl, propane-1,3-diyl or a group of the
formula --O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which
represents the point of attachment to the ring Q and represents the
point of attachment to the carboxylic acid grouping, and Q
represents cyclopentyl, cyclohexyl or phenyl, Z represents a group
of the formula ##STR00130## in which R.sup.7 represented hydrogen,
R.sup.1 represents phenyl which may be substituted by fluorine or
chlorine, and R.sup.2 represents phenyl which may be substituted by
methyl, ethyl, methoxy or ethoxy.
5. The compound as claimed in claim 1, in which B and D each
represent CH, E represents N, G represents O, A represents O or NH,
M represents a group of the formula ##STR00131## in which #
represents the point of attachment to the group A and ## represents
the point of attachment to the carboxylic acid grouping, R.sup.4
represents hydrogen or methyl, L.sup.1 represents butane-1,4-diyl,
pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid-
. in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the carboxylic acid grouping, L.sup.1A represents
methylene or ethane-1,2-diyl which may be mono- or disubstituted by
methyl, and L.sup.1B represents methylene or ethane-1,2-diyl,
L.sup.2 represents a bond or methylene, L.sup.3 represents
methylene, ethane-1,2-diyl, propane-1,3-diyl or a group of the
formula --O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which
represents the point of attachment to the ring Q and represents the
point of attachment to the carboxylic acid grouping, and Q
represents cyclopentyl, cyclohexyl or phenyl, Z represents a group
of the formula ##STR00132## in which R.sup.7 represented hydrogen,
R.sup.1 represents phenyl which may be substituted by fluorine or
chlorine, and R.sup.2 represents phenyl which may be substituted by
methyl, ethyl, methoxy or ethoxy.
6. The compound as claimed in claim 1, in which B represents N D
and E each represent CH, G represents O, A represents O or NH, M
represents a group of the formula ##STR00133## in which #
represents the point of attachment to the group A and ## represents
the point of attachment to the carboxylic acid grouping, R.sup.4
represents hydrogen or methyl, L.sup.1 represents butane-1,4-diyl,
pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid-
. in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the carboxylic acid grouping, L.sup.1A represents
methylene or ethane-1,2-diyl which may be mono- or disubstituted by
methyl, and L.sup.1B represents methylene or ethane-1,2-diyl,
L.sup.2 represents a bond or methylene, L.sup.3 represents
methylene, ethane-1,2-diyl, propane-1,3-diyl or a group of the
formula --O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which
represents the point of attachment to the ring Q and represents the
point of attachment to the carboxylic acid grouping, and Q
represents cyclopentyl, cyclohexyl or phenyl, Z represents a group
of the formula ##STR00134## in which R.sup.7 represented hydrogen,
R.sup.1 represents phenyl which may be substituted by fluorine or
chlorine, and R.sup.2 represents phenyl which may be substituted by
methyl, ethyl, methoxy or ethoxy.
7. The compound as claimed in claim 1, in which B and E each
represent N, D represents CH, G represents NH, A represents O or
NH, M represents a group of the formula ##STR00135## in which #
represents the point of attachment to the group A and ## represents
the point of attachment to the carboxylic acid grouping, R.sup.4
represents hydrogen or methyl, L.sup.1 represents butane-1,4-diyl,
pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid-
. in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the carboxylic acid grouping, L.sup.1A represents
methylene or ethane-1,2-diyl which may be mono- or disubstituted by
methyl, and L.sup.1B represents methylene or ethane-1,2-diyl,
L.sup.2 represents a bond or methylene, L.sup.3 represents
methylene, ethane-1,2-diyl, propane-1,3-diyl or a group of the
formula --O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which
represents the point of attachment to the ring Q and represents the
point of attachment to the carboxylic acid grouping, and Q
represents cyclopentyl, cyclohexyl or phenyl, Z represents a group
of the formula ##STR00136## in which R.sup.7 represented hydrogen,
R.sup.1 represents phenyl which may be substituted by fluorine or
chlorine, and R.sup.2 represents phenyl which may be substituted by
methyl, ethyl, methoxy or ethoxy.
8. The compound as claimed in claim 1, in which B and E each
represent N, D represents CH, G represents S, A represents O or NH,
M represents a group of the formula ##STR00137## in which #
represents the point of attachment to the group A and ## represents
the point of attachment to the carboxylic acid grouping, R.sup.4
represents hydrogen or methyl, L.sup.1 represents butane-1,4-diyl,
pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid-
. in which represents the point of attachment to the group
--CHR.sup.4, .diamond-solid..diamond-solid. represents the point of
attachment to the carboxylic acid grouping, L.sup.1A represents
methylene or ethane-1,2-diyl which may be mono- or disubstituted by
methyl, and L.sup.1B represents methylene or ethane-1,2-diyl,
L.sup.2 represents a bond or methylene, L.sup.3 represents
methylene, ethane-1,2-diyl, propane-1,3-diyl or a group of the
formula --O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which
represents the point of attachment to the ring Q and represents the
point of attachment to the carboxylic acid grouping, and Q
represents cyclopentyl, cyclohexyl or phenyl, Z represents a group
of the formula ##STR00138## in which R.sup.7 represented hydrogen,
R.sup.1 represents phenyl which may be substituted by fluorine or
chlorine, and R.sup.2 represents phenyl which may be substituted by
methyl, ethyl, methoxy or ethoxy.
9. A process for preparing compounds as defined in claim 1 in which
Z represents --COOH or --C(.dbd.O)--COOH, characterized in that
either [A] compounds of the formula (II) ##STR00139## in which B,
D, E, G, R.sup.1 and R.sup.2 each have the meanings given in claim
1 and X.sup.1 represents a leaving group such as, for example,
halogen, in particular chlorine, are reacted in an inert solvent in
the presence of a base with a compound of the formula (III)
##STR00140## in which A and M have the meanings given in claim 1
and Z.sup.1 represents cyano or a group of the formula
--[C(O)].sub.y--COOR.sup.7A in which y represents the number 0 or 1
and R.sup.7A represents (C.sub.1-C.sub.4)-alkyl, to give compounds
of the formula (IV) ##STR00141## in which A, B, D, E, G, M,
Z.sup.1, R.sup.1 and R.sup.2 each have the meanings given above, or
[B] compounds of the formula (V) ##STR00142## in which A, B, D, E,
G, R.sup.1 and R.sup.2 each have the meanings given in claim 1, are
reacted in an inert solvent in the presence of a base with a
compound of the formula (VI) ##STR00143## in which M has the
meanings given in claim 1 and Z.sup.1 has the meaning given above
and X.sup.2 represents a leaving group such as, for example,
halogen, mesylate, tosylate or triflate, to give compounds of the
formula (IV) ##STR00144## in which A, B, D, E, G, M, Z.sup.1,
R.sup.1 and R.sup.2 each have the meanings given above, and the
compounds of the formula (IV) are then converted by hydrolysis of
the ester or cyano group Z.sup.1 into the carboxylic acids of the
formula (Ia) ##STR00145## in which A, B, D, E, G, M, R.sup.1,
R.sup.2 and y each have the meanings given above, and these are, if
appropriate, converted into their salts using the appropriate (i)
solvents and/or (ii) bases or acids.
10-11. (canceled)
12. A medicament comprising a compound as defined in claim 1 in
combination with an inert non-toxic pharmaceutically acceptable
auxiliary.
13-14. (canceled)
15. A method for the treatment and/or prophylaxis of angina
pectoris, pulmonary hypertension, thromboembolic disorders and
peripheral occlusive diseases in humans and animals by
administering an effective amount of at least one compound as
defined in claim 1.
Description
[0001] The present application relates to novel substituted
bicyclic heteroaryl compounds, to processes for their preparation,
to their use for the treatment and/or prophylaxis of diseases and
to their use for preparing medicaments for the treatment and/or
prophylaxis of diseases, in particular for the treatment and/or
prophylaxis of cardiovascular diseases.
[0002] Prostacyclin (PGI.sub.2) belongs to the class of bioactive
prostaglandins, which are derivatives of arachidonic acid.
PGI.sub.2 is the main product of arachidonic acid metabolism in
endothelial cells and is a potent vasodilator and inhibitor of
platelet aggregation. PGI.sub.2 is the physiological antagonist of
thromboxane A.sub.2 (TxA.sub.2), a strong vasoconstrictor and
stimulator of thrombocyte aggregation, and thus contributes to the
maintenance of vascular homeostasis. A drop in PGI.sub.2 levels is
presumed to be partly responsible for the development of various
cardiovascular diseases [Dusting, G. J. et al., Pharmac. Ther.
1990, 48: 323-344; Vane, J. et al., Eur. J. Vasc. Endovasc. Surg.
2003, 26: 571-578].
[0003] After release of arachidonic acid from phospholipids via
phospholipases A.sub.2, PGI.sub.2 is synthesized by cyclooxygenases
and then by PGI.sub.2-synthase. PGI.sub.2 is not stored, but is
released immediately after synthesis, exerting its effects locally.
PGI.sub.2 is an unstable molecule, which is transformed rapidly
(half-life approx. 3 minutes) and non-enzymatically, to an inactive
metabolite, 6-keto-prostaglandin-F1alpha [Dusting, G. J. et al.,
Pharmac. Ther. 1990, 48: 323-344].
[0004] The biological effects of PGI.sub.2 occur through binding to
a membrane-bound receptor, called the prostacyclin receptor or IP
receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226].
The IP receptor is one of the G-protein-coupled receptors, which
are characterized by seven transmembrane domains. In addition to
the human IP receptor, prostacyclin receptors have also been cloned
from rat and mouse [Vane, J. et al., Eur. J. Vasc. Endovasc. Surg.
2003, 26: 571-578]. In smooth muscle cells, activation of the IP
receptor leads to stimulation of adenylate cyclase, which catalyses
the formation of cAMP from ATP. The increase in the intracellular
cAMP concentration is responsible for prostacyclin-induced
vasodilation and for inhibition of platelet aggregation. In
addition to the vasoactive properties, anti-proliferative effects
[Schroer, K. et al., Agents Actions Suppl. 1997, 48: 63-91;
Kothapalli, D. et al., Mol. Pharmacol. 2003, 64: 249-258; Planchon,
P. et al., Life Sci. 1995, 57: 1233-1240] and anti-arteriosclerotic
effects [Rudic, R. D. et al., Circ. Res. 2005, 96: 1240-1247; Egan
K. M. et al., Science 2004, 114: 784-794] have also been described
for PGI.sub.2. Furthermore, PGI.sub.2 also inhibits the formation
of metastases [Schneider, M. R. et al., Cancer Metastasis Rev.
1994, 13: 349-64]. It is unclear whether these effects are due to
stimulation of cAMP formation or to IP receptor-mediated activation
of other signal transduction pathways in the respective target cell
[Wise, H. et al. TIPS 1996, 17: 17-21], such as the
phosphoinositide cascade, and of potassium channels.
[0005] Although the effects of PGI.sub.2 are on the whole of
benefit therapeutically, clinical application of PGI.sub.2 is
severely restricted by its chemical and metabolic instability.
PGI.sub.2 analogs that are more stable, for example iloprost
[Badesch, D. B. et al., J. Am. Coll. Cardiol. 2004, 43: 56S-61S]
and treprostinil [Chattaraj, S. C., Curr. Opion. Invest. Drugs
2002, 3: 582-586] have been made available, but these compounds
still have a very short time of action. Moreover, the substances
can only be administered to the patient via complicated routes of
administration, e.g. by continuous infusion, subcutaneously or via
repeated inhalations. These routes of administration can also have
additional side-effects, for example infections or pains at the
site of injection. The use of beraprost, which to date is the only
PGI.sub.2 derivative available for oral administration to the
patient [Barst, R. J. et al., J. Am. Coll. Cardiol. 2003, 41:
2119-2125], is once again limited by its short time of action.
[0006] The compounds described in the present application are,
compared with PGI.sub.2, chemically and metabolically stable,
non-prostanoid activators of the IP receptor, which imitate the
biological action of PGI.sub.2 and can thus be used for treating
diseases, in particular cardiovascular diseases.
[0007] WO 00/75145 claims compounds having a bicyclic heteroaryl
core structure as inhibitors of cell adhesion. 4-Amino-, 4-oxy-
and/or 4-thio-substituted furo [2,3-d]-pyrimidine,
thieno[2,3-d]pyrimidine and/or pyrrolo[2,3-d]pyrimidine derivatives
and their use for treating diseases are disclosed inter alia in WO
97/02266, WO 99/07703, WO 99/65908, JP 2002-105081-A, WO 02/092603,
WO 03/018589, WO 03/022852, WO 2004/111057, WO 2005/092896, WO
2005/121149, WO 2006/004658, WO 2006/004703 and US 2007/0099877-A1.
The preparation and biological activity of diaryl-substituted
thieno[2,3-d]pyrimidines having 4-glycine or 4-alanine side chains
is reported in Bioorg. Med. Chem. 10, 3113-3122 (2002). Various
4-amino-, 4-oxy- and/or 4-thio-substituted furopyridine,
thienopyridine or pyrrolopyridine derivatives for treating diseases
are claimed, for example, in U.S. Pat. No. 6,232,320-B1, WO
2006/069080 and WO 2006/130160, and DE 29 09 754-A1 describes
certain oxy-substituted benzofuran derivatives for treating
atherosclerosis.
[0008] In contrast to the compounds of the prior art, the compounds
claimed in the context of the present invention are characterized
in that a disubstituted bicyclic heteroaryl core structure is
attached at a certain spatial distance to a carboxylic acid or a
carboxylic acid-like functionality.
[0009] The present invention provides compounds of the general
formula (I)
##STR00001##
in which [0010] B, D and E each represent CH or N, [0011] G
represents NH, O or S, with the proviso that [0012] G does not
represent O if at the same time B and E represent N and D
represents CH, [0013] and [0014] G does not represent NH or S if at
the same time B, D and E represent CH, [0015] A represents O or
N--R.sup.3 in which [0016] R.sup.3 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl or
(C.sub.4-C.sub.7)-cycloalkenyl, [0017] M represents a group of the
formula
[0017] ##STR00002## [0018] in which [0019] # represents the point
of attachment to the group A [0020] and [0021] ## represents the
point of attachment to the group Z, [0022] R.sup.4 represents
hydrogen or (C.sub.1-C.sub.4)-alkyl which may be substituted by
hydroxyl or amino, [0023] L.sup.1 represents
(C.sub.1-C.sub.7)-alkanediyl or (C.sub.2-C.sub.7)-alkenediyl which
may be mono- or disubstituted by fluorine, or represents a group of
the formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which [0024] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0025] .diamond-solid..diamond-solid.
represents the point of attachment to the group Z, [0026] L.sup.1A
represents (C.sub.1-C.sub.5)-alkanediyl which may be mono- or
disubstituted by identical or different substituents from the group
consisting of (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy,
[0027] L.sup.1B represents a bond or (C.sub.1-C.sub.3)-alkanediyl
which may be mono- or disubstituted by fluorine, [0028] and [0029]
V represents O or N--R.sup.5 in which [0030] R.sup.5 represents
hydrogen, (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0031] L.sup.2 represents a bond or (C.sub.1-C.sub.4)-alkanediyl,
[0032] L.sup.3 represents (C.sub.1-C.sub.4)-alkanediyl which may be
mono- or disubstituted by fluorine and in which a methylene group
may be replaced by O or N--R.sup.6 [0033] in which [0034] R.sup.6
represents hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl, [0035] or represents
(C.sub.2-C.sub.4)-alkenediyl, [0036] and [0037] Q represents
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.4-C.sub.7)-cycloalkenyl,
phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered
heteroaryl, each of which may be substituted by up to two identical
or different radicals selected from the group consisting of
fluorine, chlorine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl,
hydroxyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, amino,
mono-(C.sub.1-C.sub.4)-alkylamino and
di-(C.sub.1-C.sub.4)-alkylamino, where (C.sub.1-C.sub.4)-alkyl for
its part may be substituted by hydroxyl, (C.sub.1-C.sub.4)-alkoxy,
amino, mono- or di-(C.sub.1-C.sub.4)-alkylamino, [0038] Z
represents a group of the formula
[0038] ##STR00003## [0039] in which [0040] ### represents the point
of attachment to the group L.sup.1 or L.sup.3 [0041] and [0042]
R.sup.7 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, and [0043]
R.sup.1 and R.sup.2 are identical or different and independently of
one another represent (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.4-C.sub.7)-cycloalkenyl, phenyl, 5- to 7-membered
heterocyclyl or 5- or 6-membered heteroaryl each of which may be
mono- to trisubstituted by identical or different radicals selected
from the group consisting of halogen, cyano, nitro,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.4)-alkynyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.4-C.sub.7)-cycloalkenyl, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)-alkylthio,
(C.sub.1-C.sub.6)-acyl, amino, mono-(C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.1-C.sub.6)-alkylamino and (C.sub.1-C.sub.6)-acylamino,
[0044] where (C.sub.1-C.sub.6)-alkyl and (C.sub.1-C.sub.6)-alkoxy
for their part may each be substituted by cyano, hydroxyl,
(C.sub.1-C.sub.4)-alkoxy, (C.sub.1-C.sub.4)-alkylthio, amino, mono-
or di-(C.sub.1-C.sub.4)-alkylamino, or [0045] R.sup.1 and/or
R.sup.2 represent phenyl in which two radicals attached to adjacent
ring carbon atoms together form a group of the formula
--O--CH.sub.2--O--, --O--CHF--O--, --O--CF.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O-- or --O--CF.sub.2--CF.sub.2--O--, and
their salts, solvates and solvates of the salts.
[0046] Compounds according to the invention are the compounds of
the formula (I) and the salts, solvates and solvates of the salts
thereof, the compounds of the formulae below encompassed by the
formula (I) and the salts, solvates and solvates of the salts
thereof, and also the compounds encompassed by the formula (I) and
mentioned below as working examples, and the salts, solvates and
solvates of the salts thereof, provided the compounds encompassed
by formula (I) and mentioned below are not already salts, solvates
and solvates of the salts.
[0047] The compounds of the invention may, depending on their
structure, exist in stereoisomeric forms (enantiomers,
diastereomers). The present invention therefore relates to the
enantiomers or diastereomers and respective mixtures thereof. The
stereoisomerically pure constituents can be isolated in a known
manner from such mixtures of enantiomers and/or diastereomers.
[0048] If the compounds of the invention may occur in tautomeric
forms, the present invention encompasses all tautomeric forms.
[0049] Salts which are preferred for the purposes of the present
invention are physiologically acceptable salts of the compounds of
the invention. Also encompassed are salts which are themselves
unsuitable for pharmaceutical uses but can be used for example for
isolating or purifying the compounds of the invention.
[0050] Physiologically acceptable salts of the compounds of the
invention include acid addition salts of mineral acids, carboxylic
acids and sulfonic acids, e.g. salts of hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic
acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic
acid, propionic acid, lactic acid, tartaric acid, maleic acid,
citric acid, fumaric acid, maleic acid and benzoic acid.
[0051] Physiologically acceptable salts of the compounds of the
invention include salts of conventional bases such as, by way of
example and preferably, alkali metal salts (e.g. sodium and
potassium salts), alkaline earth metal salts (e.g. calcium and
magnesium salts) and ammonium salts derived from ammonia or organic
amines having 1 to 16 C atoms, such as, by way of example and
preferably, ethylamine, diethylamine, triethylamine,
ethyldiisopropylamine, monoethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,
dibenzylamine, N-methylmorpholine, arginine, lysine,
ethylenediamine and N-methylpiperidine.
[0052] Solvates refers for the purposes of the invention to those
forms of the compounds of the invention which form, in the solid or
liquid state, a complex by coordination with solvent molecules.
Hydrates are a specific form of solvates in which the coordination
takes place with water. Hydrates are preferred solvates in the
context of the present invention.
[0053] The present invention additionally encompasses the use of
prodrugs of the compounds of the invention. The term "prodrugs"
encompasses compounds which themselves may be biologically active
or inactive, but are converted during their residence time in the
body into compounds of the invention (for example by metabolism or
hydrolysis).
[0054] In particular, for the compounds of the formula (I) in
which
Z represents a group of the formula
##STR00004##
the present invention also includes hydrolyzable ester derivatives
of these compounds. These are to be understood as meaning esters
which can be hydrolyzed to the free carboxylic acids, as the
compounds that are mainly active biologically, in physiologically
media, under the conditions of the biological tests described later
and in particular in vivo by enzymatic or chemical routes.
(C.sub.1-C.sub.4)-alkyl esters, in which the alkyl group can be
straight-chain or branched, are preferred as such esters.
Particular preference is given to methyl or ethyl esters (see also
the corresponding definitions of the radical R.sup.7).
[0055] In the context of the present invention, the substituents
have the following meaning, unless specified otherwise:
[0056] (C.sub.1-C.sub.6)-Alkyl, (C.sub.1-C.sub.5)-alkyl,
(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.3)-alkyl stand in the
context of the invention for a straight-chain or branched alkyl
radical having respectively 1 to 6, 1 to 5, 1 to 4 and 1 to 3
carbon atoms. A straight-chain or branched alkyl radical having 1
to 4, in particular 1 to 3, carbon atoms is preferred. Examples
which may be preferably mentioned are: methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl,
n-pentyl and n-hexyl.
[0057] (C.sub.2-C.sub.6)-Alkenyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.4)-alkenyl stand in the context of the invention for
a straight-chain or branched alkenyl radical having respectively 2
to 6, 2 to 5 and 2 to 4 carbon atoms and one or two double bonds. A
straight-chain or branched alkenyl radical having 2 to 4 carbon
atoms and one double bond is preferred. Examples which may be
preferably mentioned are: vinyl, allyl, isopropenyl and
n-but-2-en-1-yl.
[0058] (C.sub.2-C.sub.4)-Alkynyl stands in the context of the
invention for a straight-chain or branched alkynyl radical having 2
to 4 carbon atoms and one triple bond. A straight-chain alkynyl
radical having 2 to 4 carbon atoms is preferred. Examples which may
be preferably mentioned are: ethynyl, n-prop-1-in-1-yl,
n-prop-2-in-1-yl, n-but-2-in-1-yl and n-but-3-in-1-yl.
[0059] (C.sub.1-C.sub.4)-Alkanediyl and
(C.sub.1-C.sub.3)-alkanediyl stand in the context of the invention
for a straight-chain or branched divalent alkyl radical having
respectively 1 to 4 and 1 to 3 carbon atoms. In each case, a
straight-chain alkanediyl radical having respectively 1 to 4 and 1
to 3 carbon atoms is preferred. Examples which may be preferably
mentioned are: methylene, ethane-1,2-diyl(1,2-ethylene),
ethane-1,1-diyl, propane-1,3-diyl(1,3-propylene), propane-1,1-diyl,
propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl(1,4-butylene),
butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl.
[0060] (C.sub.1-C.sub.7)-Alkanediyl, (C.sub.1-C.sub.5)-alkanediyl
and (C.sub.3-C.sub.7)-alkanediyl stand in the context of the
invention for a straight-chain or branched divalent alkyl radical
having respectively 1 to 7, 1 to 5 and 3 to 7 carbon atoms. In each
case, a straight-chain alkanediyl radical having respectively 1 to
7, 1 to 5 and 3 to 7 carbon atoms is preferred. Examples which may
be preferably mentioned are: methylene,
ethane-1,2-diyl(1,2-ethylene), ethane-1,1-diyl,
propane-1,3-diyl(1,3-propylene), propane-1,1-diyl,
propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl(1,4-butylene),
butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl,
pentane-1,5-diyl(1,5-pentylene), pentane-2,4-diyl,
3-methylpentane-2,4-diyl and hexane-1,6-diyl(1,6-hexylene).
[0061] (C.sub.2-C.sub.4)-Alkenediyl and
(C.sub.2-C.sub.3)-alkenediyl stand in the context of the invention
for a straight-chain or branched divalent alkenyl radical having
respectively 2 to 4 and 2 to 3 carbon atoms and up to 2 double
bonds. In each case, a straight-chain alkenediyl radical having
respectively 2 to 4 and 2 to 3 carbon atoms and one double bond is
preferred. Examples which may be preferably mentioned are:
ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl,
propene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl,
but-1-ene-1,3-diyl, but-2-ene-1,4-diyl and
buta-1,3-diene-1,4-diyl.
[0062] (C.sub.2-C.sub.7)-Alkenediyl and
(C.sub.3-C.sub.7)-alkenediyl stand in the context of the invention
for a straight-chain or branched divalent alkenyl radical having
respectively 2 to 7 and 3 to 7 carbon atoms and up to 3 double
bonds. In each case, a straight-chain alkenediyl radical having
respectively 2 to 7 and 3 to 7 carbon atoms and one double bond is
preferred. Examples which may be preferably mentioned are:
ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl,
propene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl,
but-1-ene-1,3-diyl, but-2-ene-1,4-diyl, buta-1,3-diene-1,4-diyl,
pent-2-ene-1,5-diyl, hex-3-ene-1,6-diyl and
hexa-2,4-diene-1,6-diyl.
[0063] (C.sub.1-C.sub.6)-Alkoxy and (C.sub.1-C.sub.4)-alkoxy stand
in the context of the invention for a straight-chain or branched
alkoxy radical having respectively 1 to 6 and 1 to 4 carbon atoms.
A straight-chain or branched alkoxy radical having 1 to 4 carbon
atoms is preferred. Examples which may be preferably mentioned are:
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
n-pentoxy and n-hexoxy.
[0064] (C.sub.1-C.sub.6)-Alkylthio and (C.sub.1-C.sub.4)-alkylthio
stand in the context of the invention for a straight-chain or
branched alkylthio radical having respectively 1 to 6 and 1 to 4
carbon atoms. A straight-chain or branched alkylthio radical having
1 to 4 carbon atoms is preferred. Examples which may be preferably
mentioned are: methylthio, ethylthio, n-propylthio, isopropylthio,
n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.
[0065] (C.sub.1-C.sub.6)-Acyl [(C.sub.1-C.sub.6)-alkanoyl],
(C.sub.1-C.sub.5)-acyl [(C.sub.1-C.sub.5)-alkanoyl] and
(C.sub.1-C.sub.4)-acyl [(C.sub.1-C.sub.4)-alkanoyl] stand in the
context of the invention for a straight-chain or branched alkyl
radical having respectively 1 to 6, 1 to 5 and 1 to 4 carbon atoms
which carries a doubly attached oxygen atom in the 1-position and
is attached via the 1-position. A straight-chain or branched acyl
radical having 1 to 4 carbon atoms is preferred. Examples which may
be preferably mentioned are: formyl, acetyl, propionyl, n-butyryl,
isobutyryl and pivaloyl.
[0066] Mono-(C.sub.1-C.sub.6)-alkylamino and
mono-(C.sub.1-C.sub.4)-alkylamino stand in the context of the
invention for an amino group having a straight-chain or branched
alkyl substituent which has respectively 1 to 6 and 1 to 4 carbon
atoms. A straight-chain or branched monoalkylamino radical having 1
to 4 carbon atoms is preferred. Examples which may be preferably
mentioned are: methylamino, ethylamino, n-propylamino,
isopropylamino and tert-butylamino.
[0067] Di-(C.sub.1-C.sub.6)-alkylamino and
di-(C.sub.1-C.sub.4)-alkylamino stand in the context of the
invention for an amino group having two identical or different
straight-chain or branched alkyl substituents having respectively 1
to 6 and 1 to 4 carbon atoms. Straight-chain or branched
dialkylamino radicals having in each case 1 to 4 carbon atoms are
preferred. Examples which may be preferably mentioned are:
N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,
N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino,
N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and
N-n-hexyl-N-methylamino.
[0068] (C.sub.1-C.sub.6)-Acylamino and (C.sub.1-C.sub.4)-acylamino
stand in the context of the invention for an amino group having a
straight-chain or branched acyl substituent which has respectively
1 to 6 and 1 to 4 carbon atoms and is attached via the carbonyl
group. An acylamino radical having 1 to 4 carbon atoms is
preferred. Examples which may be preferably mentioned are:
formamido, acetamido, propionamido, n-butyramido and
pivaloylamido.
[0069] (C.sub.3-C.sub.7)-Cycloalkyl, (C.sub.3-C.sub.6)-cycloalkyl
and (C.sub.4-C.sub.6)-cycloalkyl stand in the context of the
invention for a monocyclic saturated cycloalkyl group having
respectively 3 to 7, 3 to 6 and 4 to 6 carbon atoms. A cycloalkyl
radical having 3 to 6 carbon atoms is preferred. Examples which may
be preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
[0070] (C.sub.4-C.sub.7)-Cycloalkenyl,
(C.sub.4-C.sub.6)-cycloalkenyl and (C.sub.1-C.sub.6)-cycloalkenyl
stand in the context of the invention for a monocyclic cycloalkyl
group having respectively 4 to 7, 4 to 6 and 5 or 6 carbon atoms
and one double bond. A cycloalkenyl radical having 4 to 6,
particularly preferably 5 or 6, carbon atoms is preferred. Examples
which may be preferably mentioned are: cyclobutenyl, cyclopentenyl,
cyclohexenyl and cycloheptenyl.
[0071] 5- to 7-membered heterocyclyl stands in the context of the
invention for a saturated or partially unsaturated heterocycle
having 5 to 7 ring atoms which contains one or two ring heteroatoms
from the group consisting of N and O and is attached via ring
carbon atoms and/or, if appropriate, ring nitrogen atoms. A 5- or
6-membered saturated heterocycle having one or two ring heteroatoms
from the group consisting of N and O is preferred. Examples which
may be mentioned are: pyrrolidinyl, pyrrolinyl, pyrazolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, dihydropyranyl,
tetrahydropyranyl, morpholinyl, hexahydroazepinyl and
hexahydro-1,4-diazepinyl. Preference is given to pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and
morpholinyl.
[0072] 5- or 6-membered heteroaryl stands in the context of the
invention for an aromatic heterocycle (heteroaromatic) having 5 or
6 ring atoms which contains one or two ring heteroatoms from the
group consisting of N, O and S and is attached via ring carbon
atoms and/or, if appropriate, a ring nitrogen atom. Examples which
may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl,
pyrimidinyl, pyridazinyl and pyrazinyl. Preference is given to
thienyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
[0073] Halogen includes in the context of the invention fluorine,
chlorine, bromine and iodine. Preference is given to chlorine or
fluorine.
[0074] If radicals in the compounds according to the invention are
substituted, the radicals, unless specified otherwise, may be mono-
or polysubstituted. In the context of the present invention, for
all radicals that occur more than once, their meanings are
independent of one another. Substitution by 1, 2 or 3 identical or
different substituents is preferred. Very particular preference is
given to substitution by one substituent.
[0075] In the context of the present invention, preference is given
to compounds of the formula (I) in which the bicyclic ring
system
##STR00005##
represents a heteroaryl group of the formula
##STR00006## [0076] in which [0077] * represents the point of
attachment to the radical R.sup.1, [0078] ** represents the point
of attachment to the radical R.sup.2 [0079] and [0080] ***
represents the point of attachment to the group -A-M-Z, [0081] B, D
and E each represent CH or N, with the proviso that B does not
represent N if at the same time D represents CH and E represents N,
[0082] and [0083] G represents NH or S, [0084] A represents O or
N--R.sup.3 in which [0085] R.sup.3 represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or cyclopropyl, [0086] M represents a group
of the formula
[0086] ##STR00007## [0087] in which [0088] # represents the point
of attachment to the group A [0089] and [0090] ## represents the
point of attachment to the group Z, [0091] R.sup.4 represents
hydrogen or (C.sub.1-C.sub.3)-alkyl which may be substituted by
hydroxyl or amino, [0092] L.sup.1 represents
(C.sub.3-C.sub.7)-alkanediyl or (C.sub.3-C.sub.7)-alkenediyl which
may be mono- or disubstituted by fluorine, or a group of the
formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which [0093] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0094] .diamond-solid..diamond-solid.
represents the point of attachment to the group Z, [0095] L.sup.1A
represents (C.sub.1-C.sub.3)-alkanediyl which may be mono- or
disubstituted by identical or different substituents from the group
consisting of methyl and ethyl, [0096] L.sup.1B represents
(C.sub.1-C.sub.3)-alkanediyl which may be mono- or disubstituted by
fluorine, [0097] and [0098] V represents O or N--R.sup.5 in which
[0099] R.sup.5 represents hydrogen, (C.sub.1-C.sub.3)-alkyl or
cyclopropyl, [0100] L.sup.2 represents a bond or
(C.sub.1-C.sub.3)-alkanediyl, [0101] L.sup.3 represents
(C.sub.1-C.sub.3)-alkanediyl which may be mono- or disubstituted by
fluorine, (C.sub.2-C.sub.3)-alkenediyl or a group of the formula
--W--CR.sup.8R.sup.9-- , --W--CH.sub.2--CR.sup.8R.sup.9-- or
--CH.sub.2--W--CR.sup.8R.sup.9-- in which [0102] represents the
point of attachment to the ring Q, [0103] represents the point of
attachment to the group Z, [0104] W represents O or N--R.sup.6 in
which [0105] R.sup.6 represents hydrogen, (C.sub.1-C.sub.3)-alkyl
or cyclopropyl, [0106] and [0107] R.sup.8 and R.sup.9 independently
of one another represent hydrogen or fluorine, [0108] and [0109] Q
represents (C.sub.4-C.sub.6)-cycloalkyl,
(C.sub.4-C.sub.6)-cycloalkenyl, phenyl or 5- or 6-membered
heterocyclyl, each of which may be up substituted by up to two
identical or different radicals selected from the group consisting
of fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl, trifluoromethyl,
hydroxyl, methoxy, ethoxy, trifluoromethoxy, amino, methylamino,
ethylamino, dimethylamino and diethylamino, [0110] Z represents a
group of the formula
[0110] ##STR00008## [0111] in which [0112] ### represents the point
of attachment to the group L.sup.1 or L.sup.3 [0113] and [0114]
R.sup.7 represents hydrogen, methyl or ethyl, and [0115] R.sup.1
and R.sup.2 are identical or different and independently of one
another represent (C.sub.4-C.sub.6)-cycloalkenyl, phenyl or 5- or
6-membered heteroaryl, each of which may be mono- or disubstituted
by identical or different radicals selected from the group
consisting of fluorine, chlorine, cyano, (C.sub.1-C.sub.5)-alkyl,
(C.sub.2-C.sub.5)-alkenyl, (C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.4-C.sub.6)-cycloalkenyl, (C.sub.1-C.sub.4)-alkoxy,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.4)-alkylthio,
(C.sub.1-C.sub.5)-acyl, amino, mono-(C.sub.1-C.sub.4)-alkyl-amino,
di-(C.sub.1-C.sub.4)-alkylamino and (C.sub.1-C.sub.4)-acylamino, or
[0116] R.sup.1 and/or R.sup.2 represent phenyl in which two
radicals attached to adjacent ring carbon atoms together form a
group of the formula --O--CH.sub.2--O--, --O--CHF--O-- or
--O--CF.sub.2--O--, and to their salts, solvates and solvates of
the salts.
[0117] In the context of the present invention, particular
preference is given to compounds of the formula (I) in which the
bicyclic ring system
##STR00009##
represents a heteroaryl group of the formula
##STR00010## [0118] in which [0119] * represents the point of
attachment to the radical R.sup.1, [0120] ** represents the point
of attachment to the radical R.sup.2 [0121] and [0122] ***
represents the point of attachment to the group -A-M-Z, [0123] A
represents O or NH, [0124] M represents a group of the formula
[0124] ##STR00011## [0125] in which [0126] # represents the point
of attachment to the group A [0127] and [0128] ## represents the
point of attachment to the group Z, [0129] R.sup.4 represents
hydrogen, methyl or ethyl, [0130] L.sup.1 represents
(C.sub.3-C.sub.7)-alkanediyl, (C.sub.3-C.sub.7)-alkenediyl or a
group of the formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which [0131] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0132] .diamond-solid..diamond-solid.
represents the point of attachment to the group Z, [0133] L.sup.1A
represents (C.sub.1-C.sub.3)-alkanediyl which may be mono- or
disubstituted by methyl, [0134] L.sup.1B represents
(C.sub.1-C.sub.3)-alkanediyl [0135] and [0136] V represents O or
N--CH.sub.3, [0137] L.sup.2 represents a bond, methylene,
ethane-1,1-diyl or ethane-1,2-diyl, [0138] L.sup.3 represents
(C.sub.1-C.sub.3)-alkanediyl or a group of the formula
--W--CH.sub.2-- or --W--CH.sub.2--CH.sub.2-- in which [0139]
represents the point of attachment to the ring Q, [0140] represents
the point of attachment to the group Z [0141] and [0142] W
represents O or N--R.sup.6 in which [0143] R.sup.6 represents
hydrogen or (C.sub.1-C.sub.3)-alkyl, [0144] and [0145] Q represents
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl,
piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or
phenyl, each of which may be substituted by up to two identical or
different radicals selected from the group consisting of fluorine,
methyl, ethyl, trifluoromethyl, hydroxyl, methoxy and ethoxy,
[0146] Z represents a group of the formula
[0146] ##STR00012## [0147] in which [0148] ### represents the point
of attachment to the group L.sup.1 or L.sup.3, and [0149] R.sup.1
and R.sup.2 are identical or different and independently of one
another represent cyclopenten-1-yl, cyclohexen-1-yl, phenyl,
thienyl or pyridyl, each of which may be mono- or disubstituted by
identical or different radicals selected from the group consisting
of fluorine, chlorine, cyano, (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.4)-alkenyl, (C.sub.1-C.sub.4)-alkoxy,
trifluoromethyl and trifluoromethoxy, and to their salts, solvates
and solvates of the salts.
[0150] In the context of the present invention, special preference
is given to compounds of the formula (I-A)
##STR00013##
in which [0151] A represents O or NH, [0152] M represents a group
of the formula
[0152] ##STR00014## [0153] in which [0154] # represents the point
of attachment to the group A [0155] and [0156] ## represents the
point of attachment to the carboxylic acid grouping, [0157] R.sup.4
represents hydrogen or methyl, [0158] L.sup.1 represents
butane-1,4-diyl, pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid.
in which [0159] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0160] .diamond-solid..diamond-solid.
represents the point of attachment to the carboxylic acid grouping,
[0161] L.sup.1A represents methylene or ethane-1,2-diyl which may
be mono- or disubstituted by methyl, [0162] and [0163] L.sup.1B
represents methylene or ethane-1,2-diyl, [0164] L.sup.2 represents
a bond or methylene, [0165] L.sup.3 represents methylene,
ethane-1,2-diyl, propane-1,3-diyl or a group of the formula
--O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which [0166]
represents the point of attachment to the ring Q [0167] and [0168]
represents the point of attachment to the carboxylic acid grouping,
[0169] and [0170] Q represents cyclopentyl, cyclohexyl or phenyl,
[0171] R.sup.1 represents phenyl which may be substituted by
fluorine or chlorine, and [0172] R.sup.2 represents phenyl which
may be substituted by methyl, ethyl, methoxy or ethoxy, and to
their salts, solvates and solvates of the salts.
[0173] Special preference is also given to compounds of the formula
(I-B)
##STR00015##
in which [0174] A represents O or NH, [0175] M represents a group
of the formula
[0175] ##STR00016## [0176] in which [0177] # represents the point
of attachment to the group A [0178] and [0179] ## represents the
point of attachment to the carboxylic acid grouping, [0180] R.sup.4
represents hydrogen or methyl, [0181] L.sup.1 represents
butane-1,4-diyl, pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid.
in which [0182] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0183] .diamond-solid..diamond-solid.
represents the point of attachment to the carboxylic acid grouping,
[0184] L.sup.1A represents methylene or ethane-1,2-diyl which may
be mono- or disubstituted by methyl, [0185] and [0186] L.sup.1B
represents methylene or ethane-1,2-diyl, [0187] L.sup.2 represents
a bond or methylene, [0188] L.sup.3 represents methylene,
ethane-1,2-diyl, propane-1,3-diyl or a group of the formula
--O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which [0189]
represents the point of attachment to the ring Q [0190] and [0191]
represents the point of attachment to the carboxylic acid grouping,
[0192] and [0193] Q represents cyclopentyl, cyclohexyl or phenyl,
[0194] R.sup.1 represents phenyl which may be substituted by
fluorine or chlorine, and [0195] R.sup.2 represents phenyl which
may be substituted by methyl, ethyl, methoxy or ethoxy, and to
their salts, solvates and solvates of the salts.
[0196] Special preference is also given to compounds of the formula
(I-C)
##STR00017##
in which [0197] A represents O or NH, [0198] M represents a group
of the formula
[0198] ##STR00018## [0199] in which [0200] # represents the point
of attachment to the group A [0201] and [0202] ## represents the
point of attachment to the carboxylic acid grouping, [0203] R.sup.4
represents hydrogen or methyl, [0204] L.sup.1 represents
butane-1,4-diyl, pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid.
in which [0205] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0206] .diamond-solid..diamond-solid.
represents the point of attachment to the carboxylic acid grouping,
[0207] L.sup.1A represents methylene or ethane-1,2-diyl which may
be mono- or disubstituted by methyl, [0208] and [0209] L.sup.1B
represents methylene or ethane-1,2-diyl, [0210] L.sup.2 represents
a bond or methylene, [0211] L.sup.3 represents methylene,
ethane-1,2-diyl, propane-1,3-diyl or a group of the formula
--O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which [0212]
represents the point of attachment to the ring Q [0213] and [0214]
represents the point of attachment to the carboxylic acid grouping,
[0215] and [0216] Q represents cyclopentyl, cyclohexyl or phenyl,
[0217] R.sup.1 represents phenyl which may be substituted by
fluorine or chlorine, and [0218] R.sup.2 represents phenyl which
may be substituted by methyl, ethyl, methoxy or ethoxy, and to
their salts, solvates and solvates of the salts.
[0219] Special preference is also given to compounds of the formula
(I-D)
##STR00019##
in which [0220] A represents O or NH, [0221] M represents a group
of the formula
[0221] ##STR00020## [0222] in which [0223] # represents the point
of attachment to the group A [0224] and [0225] ## represents the
point of attachment to the carboxylic acid grouping, [0226] R.sup.4
represents hydrogen or methyl, [0227] L.sup.1 represents
butane-1,4-diyl, pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid.
in which [0228] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0229] .diamond-solid..diamond-solid.
represents the point of attachment to the carboxylic acid grouping,
[0230] L.sup.1A represents methylene or ethane-1,2-diyl which may
be mono- or disubstituted by methyl, [0231] and [0232] L.sup.1B
represents methylene or ethane-1,2-diyl, [0233] L.sup.2 represents
a bond or methylene, [0234] L.sup.3 represents methylene,
ethane-1,2-diyl, propane-1,3-diyl or a group of the formula
--O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which [0235]
represents the point of attachment to the ring Q [0236] and [0237]
represents the point of attachment to the carboxylic acid grouping,
[0238] and [0239] Q represents cyclopentyl, cyclohexyl or phenyl,
[0240] R.sup.1 represents phenyl which may be substituted by
fluorine or chlorine, and [0241] R.sup.2 represents phenyl which
may be substituted by methyl, ethyl, methoxy or ethoxy, and to
their salts, solvates and solvates of the salts.
[0242] Special preference is also given to compounds of the formula
(I-E)
##STR00021##
in which [0243] A represents O or NH, [0244] M represents a group
of the formula
[0244] ##STR00022## [0245] in which [0246] # represents the point
of attachment to the group A [0247] and [0248] ## represents the
point of attachment to the carboxylic acid grouping, [0249] R.sup.4
represents hydrogen or methyl, [0250] L.sup.1 represents
butane-1,4-diyl, pentane-1,5-diyl or a group of the formula
.diamond-solid.-L.sup.1A-O-L.sup.1B-.diamond-solid..diamond-solid.
in which [0251] .diamond-solid. represents the point of attachment
to the group --CHR.sup.4, [0252] .diamond-solid..diamond-solid.
represents the point of attachment to the carboxylic acid grouping,
[0253] L.sup.1A represents methylene or ethane-1,2-diyl which may
be mono- or disubstituted by methyl, [0254] and [0255] L.sup.1B
represents methylene or ethane-1,2-diyl, [0256] L.sup.2 represents
a bond or methylene, [0257] L.sup.3 represents methylene,
ethane-1,2-diyl, propane-1,3-diyl or a group of the formula
--O--CH.sub.2-- or --O--CH.sub.2--CH.sub.2-- in which [0258]
represents the point of attachment to the ring Q [0259] and [0260]
represents the point of attachment to the carboxylic acid grouping,
[0261] and [0262] Q represents cyclopentyl, cyclohexyl or phenyl,
[0263] R.sup.1 represents phenyl which may be substituted by
fluorine or chlorine, and [0264] R.sup.2 represents phenyl which
may be substituted by methyl, ethyl, methoxy or ethoxy, and to
their salts, solvates and solvates of the salts.
[0265] The individual definitions of radicals given in the
respective combinations and preferred combinations of radicals are,
independently of the given combination of radicals in question,
also replaced by radical definitions of other combinations.
[0266] Particular preference is given to combinations of two or
more of the preferred ranges mentioned above.
[0267] In the context of the present invention, very particular
preference is given to the compounds mentioned below: [0268]
(6R)-6-{[5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-
}heptanoic acid; [0269]
(6R)-6-{[5-(4-methoxyphenyl)-6-phenylthieno[2,3-d]pyrimidin-4-yl]oxy}hept-
anoic acid; [0270]
(6R)-6-{[5-(4-ethylphenyl)-6-phenylthieno[2,3-d]pyrimidin-4-yl]oxy}heptan-
oic acid; [0271]
(6R)-6-{[3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}heptanoic
acid; [0272]
(3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-2,2-dimet-
hylpropoxy)acetic acid; [0273]
(6R)-6-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]oxy}heptanoi-
c acid; [0274]
3-(3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-2,2-dimet-
hylpropoxy)-propanoic acid; [0275]
6-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}hexanoic
acid; [0276]
(3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}propoxy)acetic
acid; and [0277]
(6R)-6-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}heptanoic
acid, and to their salts, solvates and solvates of the salts.
[0278] The invention furthermore provides a process for preparing
the compounds of the formula (I) according to the invention in
which Z represents --COOH, characterized in that either
[A] compounds of the formula (II)
##STR00023## [0279] in which B, D, E, G, R.sup.1 and R.sup.2 each
have the meanings given above [0280] and [0281] X.sup.1 represents
a leaving group such as, for example, halogen, in particular
chlorine, [0282] are reacted in an inert solvent in the presence of
a base with a compound of the formula (III)
[0282] ##STR00024## [0283] in which A and M have the meanings given
above [0284] and [0285] Z.sup.1 represents cyano or a group of the
formula --[C(O)].sub.y--COOR.sup.7A in which [0286] y represents
the number 0 or 1 [0287] and [0288] R.sup.7A represents
(C.sub.1-C.sub.4)-alkyl, [0289] to give compounds of the formula
(IV)
[0289] ##STR00025## [0290] in which A, B, D, E, G, M, Z.sup.1,
R.sup.1 and R.sup.2 each have the meanings given above, or [B]
compounds of the formula (V)
[0290] ##STR00026## [0291] in which A, B, D, E, G, R.sup.1 and
R.sup.2 each have the meanings given above, are reacted in an inert
solvent in the presence of a base with a compound of the formula
(VI)
[0291] ##STR00027## [0292] in which M and Z.sup.1 have the meanings
given above [0293] and [0294] X.sup.2 represents a leaving group
such as, for example, halogen, mesylate, tosylate or triflate,
[0295] to give compounds of the formula (IV)
[0295] ##STR00028## [0296] in which A, B, D, E, G, M, Z.sup.1,
R.sup.1 and R.sup.2 each have the meanings given above, and the
compounds of the formula (IV) are then converted by hydrolysis of
the ester or cyano group Z.sup.1 into the carboxylic acids of the
formula (Ia)
##STR00029##
[0296] in which A, B, D, E, G, M, R.sup.1, R.sup.2 and y each have
the meanings given above, and these are, if appropriate, converted
into their solvates, salts and/or solvates of the salts using the
appropriate (i) solvents and/or (ii) bases or acids.
[0297] Inert solvents for process steps (II)+(III).fwdarw.(IV) and
(V)+(VI).fwdarw.(IV) are, for example, ethers, such as diethyl
ether, methyl tert-butyl ether, dioxane, tetrahydro-furan, glycol
dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons,
such as benzene, toluene, xylene, hexane, cyclohexane or mineral
oil fractions, halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, trichloro-ethylene,
chlorobenzene or chlorotoluene, or other solvents, such as
dimethyl-formamide (DMF), dimethyl sulfoxide (DMSO),
N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or
acetonitrile. It is also possible to use mixtures of the solvents
mentioned. Preference is given to using tetrahydrofuran, toluene,
dimethylformamide, dimethyl sulfoxide or mixtures of these
solvents.
[0298] However, if appropriate, the process steps
(II)+(III).fwdarw.(IV) and (V)+(VI).fwdarw.(IV) can also be carried
out in the absence of a solvent.
[0299] Suitable bases for the process steps (II)+(III).fwdarw.(IV)
and (V)+(VI).fwdarw.(IV) are customary inorganic or organic bases.
These preferably include alkali metal hydroxides, such as, for
example, lithium hydroxide, sodium hydroxide, or potassium
hydroxide, alkali metal or alkaline earth metal carbonates, such as
lithium carbonate, sodium carbonate, potassium carbonate, calcium
carbonate or cesium carbonate, alkali metal alkoxides, such as
sodium tert-butoxide or potassium tert-butoxide, alkali metal
hydrides, such as sodium hydride or potassium hydride, amides, such
as lithium bis(trimethylsilyl)amide or potassium
bis(trimethylsilyl)amide or lithium diisopropylamide, organic
metallic compounds, such as butyllithium or phenyllithium, or
organic amines, such as triethylamine, N-methylmorpholine,
N-methylpiperidine, N,N-diisopropylethylamine or pyridine.
[0300] In the case of the reaction with alcohol derivatives [A in
(III) and (V)=O], phosphazene bases (so-called "Schwesinger
bases"), such as, for example, P2-t-Bu or P4-t-Bu are likewise
expedient [cf., for example, R. Schwesinger, H. Schlemper, Angew.
Chem. Int. Ed. Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach,
Chem. Ber. 124, 1837 (1991)].
[0301] In the reaction with amine derivatives [A in (III) and
(V)=N], the base used is preferably a tertiary amine, such as, in
particular, N,N-diisopropylethylamine or sodium tert-butoxide.
However, if appropriate, these reactions can--if an excess of the
amine component (III) is used--also be carried out without the
addition of an auxiliary base. In the reaction with alcohol
derivatives [A in (III)=O], preference is given to sodium hydride,
potassium carbonate or cesium carbonate or the phosphazene bases
P2-t-Bu and P4-t-Bu.
[0302] If appropriate, the process steps (II)+(III).fwdarw.(IV) and
(V)+(VI).fwdarw.(IV) can advantageously be carried out with
addition of a crown ether.
[0303] In one process variant, the reactions (II)+(III).fwdarw.(IV)
and (V)+(VI).fwdarw.(IV) can also be carried out in a two-phase
mixture consisting of an aqueous alkali metal hydroxide solution as
base and one of the hydrocarbons or halogenated hydrocarbons
mentioned above as further solvent, using a phase-transfer
catalyst, such as tetrabutylammonium hydrogen sulfate or
tetrabutylammonium bromide.
[0304] The process steps (II)+(III).fwdarw.(IV) and
(V)+(VI).fwdarw.(IV) are, in the reaction with amine derivatives [A
in (III) and (V)=N], generally carried out in a temperature range
of from +50.degree. C. to +200.degree. C., preferably at from
+80.degree. C. to +150.degree. C. In the reaction with alcohol
derivatives [A in (III) and (V)=O], the reactions are generally
carried out in a temperature range of from -20.degree. C. to
+120.degree. C., preferably at from 0.degree. C. to +80.degree. C.
The hydrolysis of the ester or nitrile group Z.sup.1 in process
step (IV)--(Ia) is carried out by customary methods by treating the
esters or nitriles in inert solvents with acids or bases, where in
the latter case the salts initially formed are converted by
treatment with acid into the free carboxylic acids. In the case of
the tert-butyl esters, the ester cleavage is preferably carried out
using acids.
[0305] Suitable inert solvents for these reactions are water or the
organic solvents customary for ester cleavage. These preferably
include alcohols, such as methanol, ethanol, n-propanol,
isopropanol, n-butanol or tert-butanol, or ethers, such as diethyl
ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other
solvents, such as acetone, dichloromethane, dimethylformamide or
dimethyl sulfoxide. It is also possible to use mixtures of the
solvents mentioned. In the case of a basic ester hydrolysis,
preference is given to using mixtures of water with dioxane,
tetrahydrofuran, methanol and/or ethanol, and for nitrile
hydrolysis, preference is given to using water and/or n-propanol.
In the case of the reaction with trifluoroacetic acid, preference
is given to using dichloromethane, and in the case of the reaction
with hydrogen chloride, preference is given to using
tetrahydrofuran, diethyl ether, dioxane or water.
[0306] Suitable bases are the customary inorganic bases. These
preferably include alkali metal hydroxides or alkaline earth metal
hydroxides, such as, for example, sodium hydroxide, lithium
hydroxide, potassium hydroxide or barium hydroxide, or alkali metal
carbonates or alkaline earth metal carbonates, such as sodium
carbonate, potassium carbonate or calcium carbonate. Particular
preference is given to sodium hydroxide or lithium hydroxide.
[0307] Acids suitable for the ester cleavage are, in general,
sulfuric acid, hydrogen chloride/hydrochloric acid, hydrogen
bromide/hydrobromic acid, phosphoric acid, acetic acid,
trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or
trifluoromethanesulfonic acid, or mixtures thereof, if appropriate
with added water. Preference is given to hydrogen chloride or
trifluoroacetic acid in the case of the tert-butyl esters and to
hydrochloric acid in the case of the methyl esters.
[0308] The ester cleavage is generally carried out in a temperature
range of from 0.degree. C. to +100.degree. C., preferably at from
+0.degree. C. to +50.degree. C. The nitrile hydrolysis is generally
carried out in a temperature range of from +50.degree. C. to
+150.degree. C., preferably at from +80.degree. C. to +120.degree.
C.
[0309] Reactions mentioned can be carried out at atmospheric,
elevated or reduced pressure (for example from 0.5 to 5 bar). In
general, reactions are carried out at atmospheric pressure.
[0310] The compounds of the formula (I) according to the invention
in which Z represents a group of the formula
##STR00030##
can be prepared by reacting compounds of the formula (IV) in which
Z.sup.1 represents cyano in an inert solvent with an alkali metal
azide in the presence of ammonium chloride or with trimethylsilyl
azide, if appropriate in the presence of a catalyst.
[0311] Inert solvents for this reaction are, for example, ethers,
such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl
ether or diethylene glycol dimethyl ether, hydrocarbons, such as
benzene, toluene, xylene, hexane, cyclohexane or mineral oil
fractions, or other solvents, such as dimethyl sulfoxide,
dimethylformamide, N,N'-dimethylpropyleneurea (DMPU) or
N-methylpyrrolidone (NMP). It is also possible to use mixtures of
the solvents mentioned. Preference is given to using toluene.
[0312] A suitable azide reagent is in particular sodium azide in
the presence of ammonium chloride or trimethylsilyl azide. The
latter reaction can advantageously be carried out in the presence
of a catalyst. Suitable for this purpose are in particular
compounds such as di-n-butyltin oxide, trimethylaluminum or zinc
bromide. Preference is given to using trimethylsilyl azide in
combination with di-n-butyltin oxide.
[0313] The reaction is generally carried out in a temperature range
of from +50.degree. C. to +150.degree. C., preferably at from
+60.degree. C. to +110.degree. C. The reaction can be carried out
at atmospheric, elevated or reduced pressure (for example from 0.5
to 5 bar). In general, the reaction is carried out at atmospheric
pressure.
[0314] The compounds of the formula (I) according to the invention
in which Z represents a group of the formula
##STR00031##
can be prepared by converting compounds of the formula (IV) in
which Z.sup.1 represents methoxycarbonyl or ethoxycarbonyl [y=0]
initially in an inert solvent with hydrazine into compounds of the
formula (VII)
##STR00032##
in which A, B, D, E, G, M, R.sup.1 and R.sup.2 each have the
meanings given above, and then in an inert solvent with phosgene or
a phosgene equivalent, such as, for example, N,N'-carbonyl
diimidazole.
[0315] Suitable inert solvents for the first step of this reaction
sequence are in particular alcohols, such as methanol, ethanol,
n-propanol, isopropanol, n-butanol or tert-butanol, or ethers, such
as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether
or diethylene glycol dimethyl ether. It is also possible to use
mixtures of these solvents. Preference is given to using a mixture
of methanol and tetrahydrofuran. The second reaction step is
preferably carried out in an ether, in particular in
tetrahydrofuran. The reactions are generally carried out in a
temperature range of from 0.degree. C. to +70.degree. C., under
atmospheric pressure.
[0316] The compounds of the formula (I) according to the invention
in which L.sup.1 represents a group of the formula
.diamond-solid.-L.sup.1A-V-L.sup.1B-.diamond-solid..diamond-solid.
in which L.sup.1A, L.sup.1B and V have the meanings given above can
alternatively also be prepared by converting compounds of the
formula (VIII)
##STR00033##
in which A, B, D, E, G, L.sup.1A, V, R.sup.1, R.sup.2 and R.sup.4
each have the meanings given above in the presence of a base, if
appropriate in an inert solvent, with a compound of the formula
(IX)
##STR00034##
in which L.sup.1B and Z.sup.1 have the meanings given above and
X.sup.3 represents a leaving group, such as, for example, halogen,
mesylate, tosylate or triflate, or, in the case that L.sup.1B
represents --CH.sub.2CH.sub.2-- with a compound of the formula
(X)
##STR00035##
in which Z.sup.1 has the meaning given above, into compounds of the
formula (IV-A)
##STR00036##
in which A, B, D, E, G, L.sup.1A, L.sup.1B, V, Z.sup.1, R.sup.1,
R.sup.2 and R.sup.4 each have the meanings given above, and then
reacting these further, in a manner corresponding to the process
described above.
[0317] The compounds of the formula (VIII) can--analogously to the
preparation of the compounds (IV)--be obtained by base-catalyzed
reaction of a compound of the formula (II) or (V) with a compound
of the formula (XI) or (XII)
##STR00037##
in which A, L.sup.1A, V and R.sup.4 each have the meanings given
above, T represents hydrogen or a temporary O- or N-protective
group and X.sup.4 represents a leaving group, such as, for example,
halogen, mesylate, tosylate or triflate, (cf. also Reaction Schemes
1 and 2 below).
[0318] In an analogous manner, the compounds of the formula (I)
according to the invention in which L.sup.3 represents a group of
the formula --W--CR.sup.8R.sup.9-- or
--W--CH.sub.2--CR.sup.8R.sup.9-- in which W, R.sup.8 and R.sup.9
have the meanings given above can also be prepared by converting
compounds of the formula (XIII)
##STR00038##
in which A, B, D, E, G, L.sup.2, Q, W, R.sup.1 and R.sup.2 each
have the meanings given above, in the presence of a base, if
appropriate in an inert solvent, with a compound of the formula
(XIV)
X.sup.5--(CH.sub.2).sub.m--CR.sup.8R.sup.9--Z.sup.1 (XIV),
in which R.sup.8, R.sup.9 and Z.sup.1 each have the meanings given
above, m represents the number 0 or 1 and X.sup.5 represents a
leaving group, such as, for example, halogen, mesylate, tosylate or
triflate, or in the case that L.sup.3 represents
--W--CH.sub.2CH.sub.2-- with a compound of the formula (X)
##STR00039##
in which Z.sup.1 has the meaning given above, into compounds of the
formula (IV-B)
##STR00040##
in which A, B, D, E, G, L.sup.2, Q, W, Z.sup.1, R.sup.1, R.sup.2,
R.sup.8, R.sup.9 and m each have the meanings given above, and then
reacting these further according to one of the processes described
above.
[0319] The compounds of the formula (XIII) can--analogously to the
preparation of the compounds (IV)--be obtained by base-catalyzed
reaction of a compound of the formula (II) or (V) with a compound
of the formula (XV) or (XVI)
##STR00041##
in which A, L.sup.2, Q and W each have the meanings given above, T
represents hydrogen or a temporary O- or N-protective group and
X.sup.6 represents a leaving group, such as, for example, halogen,
mesylate, tosylate or triflate, (cf. also Reaction Schemes 1 and 2
below).
[0320] For the process steps (VIII)+(IX) and (X).fwdarw.(IV-A),
(II)+(XI).fwdarw.(VIII), (V)+(XII).fwdarw.(VIII), (XIII)+(XIV) and
(X).fwdarw.(IV-B), (II)+(XV).fwdarw.(XIII) and
(V)+(XVI).fwdarw.(XIII), the reaction parameters described above
for the reactions (II)+(III).fwdarw.(IV) and (V)+(VI).fwdarw.(IV),
such as solvents, bases and reaction temperatures, are used in an
analogous manner.
[0321] The compounds of the formulae (II) and (V) are known from
the literature or can be prepared analogously to methods described
in the literature (see also Reaction schemes 3-10 below and the
literature cited therein).
[0322] The compounds of the formulae (III), (VI), (IX), (X), (XI),
(XII), (XIV), (XV) and (XVI) are commercially available, known from
the literature or can be prepared analogously to processes known
from the literature.
[0323] The preparation of the compounds according to the invention
can be illustrated by way of example by the synthesis schemes
below:
##STR00042##
##STR00043##
##STR00044##
##STR00045##
##STR00046##
##STR00047##
##STR00048##
##STR00049##
##STR00050##
##STR00051##
[0324] The compounds according to the invention possess valuable
pharmacological properties and can be used for the prevention and
treatment of diseases in humans and animals. The compounds
according to the invention are chemically and metabolically
stabile, non-prostanoid activators of the IP receptor.
[0325] They are thus suitable in particular for the prophylaxis
and/or treatment of cardiovascular diseases such as stable and
unstable angina pectoris, of hypertension and heart failure,
pulmonary hypertension, for the prophylaxis and/or treatment of
thromboembolic diseases and ischaemias such as myocardial
infarction, stroke, transient and ischaemic attacks and
subarachnoid haemorrhage, and for the prevention of restenosis such
as after thrombolytic treatments, percutaneous transluminal
angioplasty (PTA), coronary angioplasty (PTCA) and bypass
surgery.
[0326] The compounds according to the invention are particularly
suitable for the treatment and/or prophylaxis of pulmonary
hypertension (PH) including its various manifestations. The
compounds of the invention are therefore particularly suitable for
the treatment and/or prophylaxis of pulmonary arterial hypertension
(PAH) and its subtypes such as idiopathic and familial pulmonary
arterial hypertension, and the pulmonary arterial hypertension
which is associated for example with portal hypertension, fibrotic
disorders, HIV infection or inappropriate medications or
toxins.
[0327] The compounds of the invention can also be used for the
treatment and/or prophylaxis of other types of pulmonary
hypertension. Thus, for example, they can be employed for the
treatment and/or prophylaxis of pulmonary hypertension associated
with left atrial or left ventricular disorders and with left heart
valve disorders. In addition, the compounds of the invention are
suitable for the treatment and/or prophylaxis of pulmonary
hypertension associated with chronic obstructive pulmonary disease,
interstitial pulmonary disease, pulmonary fibrosis, sleep apnoea
syndrome, disorders with alveolar hypoventilation, altitude
sickness and pulmonary development impairments.
[0328] The compounds of the invention are furthermore suitable for
the treatment and/or prophylaxis of pulmonary hypertension based on
chronic thrombotic and/or embolic disorders such as, for example,
thromboembolism of the proximal pulmonary arteries, obstruction of
the distal pulmonary arteries and pulmonary embolism. The compounds
of the invention can further be used for the treatment and/or
prophylaxis of pulmonary hypertension connected with sarcoidosis,
histiocytosis X or lymphangioleiomyomatosis, and where the
pulmonary hypertension is caused by external compression of vessels
(lymph nodes, tumor, fibrosing mediastinitis).
[0329] In addition, the compounds according to the invention can
also be used for the treatment and/or prophylaxis of peripheral and
cardial vascular diseases, peripheral occlusive diseases (PAOD,
PVD) and disturbances of peripheral blood flow.
[0330] Furthermore, the compounds according to the invention can be
used for the treatment of arteriosclerosis, hepatitis, asthmatic
diseases, chronic obstructive pulmonary diseases (COPD), pulmonary
edema, fibrosing lung diseases such as idiopathic pulmonary
fibrosis (IPF) and ARDS, inflammatory vascular diseases such as
scleroderma and lupus erythematosus, renal failure, arthritis and
osteoporosis, and also for the prophylaxis and/or treatment of
cancers, especially of metastasizing tumors.
[0331] Moreover, the compounds according to the invention can also
be used as an addition to the preserving medium of an organ
transplant, e.g. kidneys, lungs, heart or islet cells.
[0332] The present invention further relates to the use of the
compounds according to the invention for the treatment and/or
prophylaxis of diseases, and especially of the aforementioned
diseases.
[0333] The present invention further relates to the use of the
compounds according to the invention for the production of a
medicinal product for the treatment and/or prophylaxis of diseases,
and especially of the aforementioned diseases.
[0334] The present invention further relates to a method for the
treatment and/or prophylaxis of diseases, especially of the
aforementioned diseases, using an effective amount of at least one
of the compounds according to the invention.
[0335] The compounds of the invention can be employed alone or, if
required, in combination with other active ingredients. The present
invention further relates to medicaments comprising at least one of
the compounds of the invention and one or more further active
ingredients, especially for the treatment and/or prophylaxis of the
aforementioned disorders. Suitable active ingredients for
combinations are by way of example and preferably: [0336] organic
nitrates and NO donors such as, for example, sodium nitroprusside,
nitroglycerin, isosorbide mononitrate, isosorbide dinitrate,
molsidomine or SIN-1, and inhaled NO; [0337] compounds which
inhibit the degradation of cyclic guanosine monophosphate (cGMP)
and/or cyclic adenosine monophosphate (cAMP), such as, for example,
inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5,
especially PDE 5 inhibitors such as sildenafil, vardenafil and
tadalafil; [0338] NO-independent but heme-dependent stimulators of
guanylate cyclase such as in particular the compounds described in
WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451; [0339] NO--
and heme-independent activators of guanylate cyclase, such as in
particular the compounds described in WO 01/19355, WO 01/19776, WO
01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; [0340]
compounds which inhibit human neutrophile elastase (HNE), such as,
for example, sivelestat, DX-890 (Reltran), elafin or in particular
the compounds described in WO 03/053930, WO 2004/020410, WO
2004/020412, WO 2004/024700, WO 2004/024701, WO 2005/080372, WO
2005/082863 and WO 2005/082864; [0341] compounds which inhibit the
signal transduction cascade, for example and preferably from the
group of kinase inhibitors, in particular from the group of
tyrosine kinase and/or serine/threonine kinase inhibitors; [0342]
compounds which inhibit soluble epoxide hydrolase (sEH), such as,
for example, N,N'-dicyclohexylurea,
12-(3-adamantan-1-yl-ureido)dodecanoic acid or
1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea; [0343]
compounds which influence the energy metabolism of the heart, such
as by way of example and preferably etomoxir, dichloroacetate,
ranolazine or trimetazidine; [0344] agonists of VPAC receptors,
such as by way of example and preferably the vasocactive intestinal
polypeptide (VIP); [0345] agents having an antithrombotic effect,
for example and preferably from the group of platelet aggregation
inhibitors, of anticoagulants or of profibrinolytic substances;
[0346] active ingredients which lower blood pressure, for example
and preferably from the group of calcium antagonists, angiotensin
All antagonists, ACE inhibitors, endothelin antagonists, renin
inhibitors, alpha-receptor blockers, beta-receptor blockers,
mineralocorticoid receptor antagonists, Rho kinase inhibitors and
diurectics; and/or [0347] active ingredients which alter lipid
metabolism, for example and preferably from the group of thyroid
receptor agonists, cholesterol synthesis inhibitors such as by way
of example and preferably HMG-CoA reductase inhibitors or squalene
synthesis inhibitors, of ACAT inhibitors, CETP inhibitors, MTP
inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,
cholesterol absorption inhibitors, lipase inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors and
lipoprotein(a) antagonists.
[0348] In a preferred embodiment of the invention, the compounds of
the invention are employed in combination with a kinase inhibitor
such as by way of example and preferably bortezomib, canertinib,
erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib,
lonafarnib, pegaptinib, pelitinib, semaxanib, sorafenib, sunitinib,
tandutinib, tipifarnib, vatalanib, fasudil, lonidamine,
leflunomide, or Y-27632.
[0349] Agents having an antithrombotic effect preferably mean
compounds from the group of platelet aggregation inhibitors, of
anticoagulants or of profibrinolytic substances.
[0350] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a platelet
aggregation inhibitor such as by way of example and preferably
aspirin, clopidogrel, ticlopidine or dipyridamole.
[0351] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a thrombin
inhibitor such as by way of example and preferably ximelagatran,
melagatran, bivalirudin or clexane.
[0352] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a GPIIb/IIIa
antagonist such as by way of example and preferably tirofiban or
abciximab.
[0353] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a factor Xa
inhibitor such as by way of example and preferably rivaroxaban,
DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112,
YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906,
JTV 803, SSR-126512 or SSR-128428.
[0354] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with heparin or a low
molecular weight (LMW) heparin derivative.
[0355] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a vitamin K
antagonist such as by way of example and preferably coumarin.
[0356] Agents which lower blood pressure preferably mean compounds
from the group of calcium antagonists, angiotensin All antagonists,
ACE inhibitors, endothelin antagonists, renin inhibitors,
alpha-receptor blockers, beta-receptor blockers, mineralocorticoid
receptor antagonists, Rho kinase inhibitors, and diuretics.
[0357] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a calcium
antagonist such as by way of example and preferably nifedipine,
amlodipine, verapamil or diltiazem.
[0358] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an alpha-1
receptor blocker such as by way of example and preferably
prazosin.
[0359] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a beta-receptor
blocker such as by way of example and preferably propranolol,
atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol,
bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol,
metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol,
labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or
bucindolol.
[0360] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an angiotensin
All antagonist such as by way of example and preferably losartan,
candesartan, valsartan, telmisartan or embusartan.
[0361] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an ACE inhibitor
such as by way of example and preferably enalapril, captopril,
lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril
or trandopril.
[0362] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an endothelin
antagonist such as by way of example and preferably bosentan,
darusentan, ambrisentan or sitaxsentan.
[0363] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a renin
inhibitor such as by way of example and preferably aliskiren,
SPP-600 or SPP-800.
[0364] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a
mineralocorticoid receptor antagonist such as by way of example and
preferably spironolactone or eplerenone.
[0365] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a Rho kinase
inhibitor such as by way of example and preferably fasudil,
Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095,
SB-772077, GSK-269962A or BA-1049.
[0366] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a diuretic such
as by way of example and preferably furosemide.
[0367] Agents which alter lipid metabolism preferably mean
compounds from the group of CETP inhibitors, thyroid receptor
agonists, cholesterol synthesis inhibitors such as HMG-CoA
reductase inhibitors or squalene synthesis inhibitors, of ACAT
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-delta agonists, cholesterol absorption inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors, lipase
inhibitors and lipoprotein(a) antagonists.
[0368] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a CETP inhibitor
such as by way of example and preferably torcetrapib (CP-529 414),
JJT-705 or CETP vaccine (Avant).
[0369] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a thyroid
receptor agonist such as by way of example and preferably
D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome
(CGS 26214).
[0370] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an HMG-CoA
reductase inhibitor from the class of statins such as by way of
example and preferably lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, rosuvastatin, cerivastatin or
pitavastatin.
[0371] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a squalene
synthesis inhibitor such as by way of example and preferably
BMS-188494 or TAK-475.
[0372] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an ACAT
inhibitor such as by way of example and preferably avasimibe,
melinamide, pactimibe, eflucimibe or SMP-797.
[0373] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an MTP inhibitor
such as by way of example and preferably implitapide, BMS-201038,
R-103757 or JTT-130.
[0374] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a PPAR-gamma
agonist such as by way of example and preferably pioglitazone or
rosiglitazone.
[0375] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a PPAR-delta
agonist such as by way of example and preferably GW-501516 or BAY
68-5042.
[0376] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a cholesterol
absorption inhibitor such as by way of example and preferably
ezetimibe, tiqueside or pamaqueside.
[0377] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a lipase
inhibitor such as by way of example and preferably orlistat.
[0378] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a polymeric bile
acid adsorbent such as by way of example and preferably
cholestyramine, colestipol, colesolvam, CholestaGel or
colestimide.
[0379] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a bile acid
reabsorption inhibitor such as by way of example and preferably
ASBT (=IBAT) inhibitors such as, for example, AZD-7806, S-8921,
AK-105, BARI-1741, SC-435 or SC-635.
[0380] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a lipoprotein(a)
antagonist such as by way of example and preferably gemcabene
calcium (CI-1027) or nicotinic acid.
[0381] The present invention further relates to medicaments
comprising at least one of the compounds according to the
invention, usually in combination with one or more inert,
non-toxic, pharmaceutically suitable excipients, and their use for
the purposes mentioned above.
[0382] The compounds of the invention may have systemic and/or
local effects. For this purpose, they can be administered in a
suitable way such as, for example, by the oral, parenteral,
pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal,
transdermal, conjunctival or otic route or as implant or stent.
[0383] The compounds of the invention can be administered in
administration forms suitable for these administration routes.
[0384] Suitable for oral administration are administration forms
which function according to the prior art and deliver the compounds
of the invention rapidly and/or in a modified manner, and which
contain the compounds of the invention in crystalline and/or
amorphized and/or dissolved form, such as, for example, tablets
(uncoated and coated tablets, for example having coatings which are
resistant to gastric juice or are insoluble or dissolve with a
delay and control the release of the compound of the invention),
tablets which disintegrate rapidly in the mouth, or films/wafers,
films/lyophilizates, capsules (for example hard or soft gelatin
capsules), sugar-coated tablets, granules, pellets, powders,
emulsions, suspensions, aerosols or solutions.
[0385] Parenteral administration can take place with avoidance of
an absorption step (e.g. intravenous, intraarterial, intracardiac,
intraspinal or intralumbar) or with inclusion of an absorption
(e.g. intramuscular, subcutaneous, intracutaneous, percutaneous, or
intraperitoneal). Administration forms suitable for parenteral
administration are, inter alia, preparations for injection and
infusion in the form of solutions, suspensions, emulsions,
lyophilizates or sterile powders.
[0386] Suitable for the other routes of administration are, for
example, pharmaceutical forms for inhalation (inter alia powder
inhalers, nebulizers), nasal drops, solutions or sprays; tablets
for lingual, sublingual or buccal administration, films/wafers or
capsules, suppositories, preparations for the ears and eyes,
vaginal capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (for example patches), milk, pastes, foams, dusting
powders, implants or stents.
[0387] Oral or parenteral administration are preferred, especially
oral and intravenous administration.
[0388] The compounds of the invention can be converted into the
stated administration forms. This can take place in a manner known
per se by mixing with inert, non-toxic, pharmaceutically suitable
excipients. These excipients include inter alia carriers (for
example microcrystalline cellulose, lactose, mannitol), solvents
(e.g. liquid polyethylene glycols), emulsifiers and dispersants or
wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan
oleate), binders (for example polyvinylpyrrolidone), synthetic and
natural polymers (for example albumin), stabilizers (e.g.
antioxidants such as, for example, ascorbic acid), colorings (e.g.
inorganic pigments such as, for example, iron oxides) and masking
flavors and/or odors.
[0389] It has generally proved to be advantageous on parenteral
administration to administer amounts of about 0.001 to 1 mg/kg,
preferably about 0.01 to 0.5 mg/kg of body weight to achieve
effective results. On oral administration, the dosage is about 0.01
to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and very
particularly preferably 0.1 to 10 mg/kg of body weight.
[0390] It may nevertheless be necessary where appropriate to
deviate from the stated amounts, in particular as a function of
body weight, administration route, individual response to the
active ingredient, type of preparation and time or interval over
which administration takes place. Thus, in some cases it may be
sufficient to make do with less than the aforementioned minimum
amount, whereas in other cases the upper limit mentioned must be
exceeded. Where relatively large amounts are administered, it may
be advisable to distribute these in a plurality of single doses
over the day.
[0391] The following exemplary embodiments illustrate the
invention. The invention is not restricted to the examples.
[0392] The percentage data in the following tests and examples are,
unless indicated otherwise, percentages by weight; parts are parts
by weight. Solvent ratios, dilution ratios and concentration data
of liquid/liquid solutions are, unless indicated otherwise, based
in each case on the volume.
A. EXAMPLES
Abbreviations
[0393] abs. absolute Ac acetyl aq. aqueous, aqueous solution Boc
tert-butoxycarbonyl Bu butyl c concentration CAN cerium(IV)
ammonium nitrate TLC thin-layer chromatography DCI direct chemical
ionization (in MS) DIBAH diisobutylaluminum hydride DIEA
diisopropylethylamine ("Hunig base")
DMAP 4-N,N-dimethylaminopyridine
[0394] DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
[0395] DMSO dimethyl sulfoxide ee enantiomeric excess EI electron
impact ionization (in MS) eq equivalent(s) ESI electrospray
ionization (in MS) Et ethyl m.p. melting point GC-MS gas
chromatography-coupled mass spectrometry sat. saturated h hour(s)
HPLC high pressure liquid chromatography cat. catalytic conc.
concentrated LC-MS liquid chromatography-coupled mass spectrometry
Me methyl min minute(s) Ms methanesulfonyl (mesyl) MS mass
spectrometry
NBS N-bromosuccinimide
[0396] NMR nuclear magnetic resonance spectrometry p-TsOH
para-toluenesulfonic acid Pd/C palladium on activated carbon Ph
phenyl rac. racemic RP reversed phase (in HPLC) RT room temperature
R.sub.t retention time (in HPLC) TFA trifluoroacetic acid THF
tetrahydrofuran
LC-MS and GC-MS Methods:
Method 1 (LC-MS):
[0397] MS instrument type: Micromass ZQ; HPLC instrument type: HP
1100 Series; UV DAD; column: Phenomenex Gemini 3.mu. 30
mm.times.3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50%
strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of
50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.2.5 min
30% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; flow rate: 0.0 min 1
ml/min.fwdarw.2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50.degree.
C.; UV detection: 210 nm.
Method 2 (LC-MS):
[0398] Instrument: Micromass Quattro LCZ with HPLC Agilent Serie
1100; column: Phenomenex Onyx Monolithic C18, 100 mm.times.3 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.2 min 65% A.fwdarw.4.5 min 5%
A.fwdarw.6 min 5% A; flow rate: 2 ml/min; oven: 40.degree. C.; UV
detection: 208-400 nm.
Method 3 (LC-MS):
[0399] MS instrument type: Waters ZQ; HPLC instrument type: Waters
Alliance 2795; column: Phenomenex Onyx Monolithic C18, 100
mm.times.3 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength
formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%
strength formic acid; gradient: 0.0 min 90% A.fwdarw.2 min 65%
A.fwdarw.4.5 min 5% A.fwdarw.6 min 5% A; flow rate: 2 ml/min; oven:
40.degree. C.; UV detection: 210 nm.
Method 4 (LC-MS):
[0400] Instrument: Micromass Quattro LCZ with HPLC Agilent Serie
1100; column: Phenomenex Synergi 2.5.mu. MAX-RP 100A Mercury, 20
mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength
formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%
strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90%
A.fwdarw.3.0 min 5% A.fwdarw.4.0 min 5% A.fwdarw.4.1 min 90% A;
flow rate: 2 ml/min; oven: 50.degree. C.; UV detection: 208-400
nm.
Method 5 (LC-MS):
[0401] MS instrument type: Micromass ZQ; HPLC instrument type:
Waters Alliance 2795; column: Phenomenex Synergi 2.5.mu. MAX-RP
100A Mercury, 20 mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml
of 50% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min
90% A.fwdarw.0.1 min 90% A.fwdarw.3.0 min 5% A.fwdarw.4.0 min 5%
A.fwdarw.4.01 min 90% A; flow rate: 2 ml/min; oven: 50.degree. C.;
UV detection: 210 nm.
Method 6 (GC-MS):
[0402] Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15
m.times.200 .mu.m.times.0.33 .mu.m; constant helium flow: 0.88
ml/min; oven: 70.degree. C.; inlet: 250.degree. C.; gradient:
70.degree. C., 30.degree. C./min.fwdarw.310.degree. C. (maintained
for 3 min).
Method 7 (LC-MS):
[0403] MS instrument type: Micromass ZQ; HPLC instrument type:
Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e
100.times.4.6 mm; mobile phase A: water+500 .mu.l 50% strength
formic acid/l, mobile phase B: acetonitrile+500 .mu.l 50% strength
formic acid/l; gradient: 0.0 min 10% B.fwdarw.7.0 min 95%
B.fwdarw.9.0 min 95% B; oven: 35.degree. C.; flow rate: 0.0 min 1.0
ml/min.fwdarw.7.0 min 2.0 ml/min.fwdarw.9.0 min 2.0 ml/min; UV
detection: 210 nm.
Method 8 (LC-MS):
[0404] Instrument: Micromass Plattform LCZ with HPLC Agilent Serie
1100; column: Thermo Hypersil GOLD 3.mu. 20 mm.times.4 mm; mobile
phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile
phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;
gradient: 0.0 min 100% A.fwdarw.0.2 min 100% A.fwdarw.2.9 min 30%
A.fwdarw.3.1 min 10% A.fwdarw.5.5 min 10% A; oven: 50.degree. C.;
flow rate: 0.8 ml/min; UV detection: 210 nm.
Method 9 (LC-MS):
[0405] Instrument: Micromass Quattro LCZ with HPLC Agilent Serie
1100; column: Phenomenex Synergi 2.mu. Hydro-RP Mercury 20
mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength
formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%
strength formic acid; gradient: 0.0 min 90% A.fwdarw.2.5 min 30%
A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; flow rate: 0.0 min 1
ml/min.fwdarw.2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50.degree.
C.; UV detection: 208-400 nm.
Method 10 (LC-MS):
[0406] Instrument: Micromass QuattroPremier with Waters HPLC
Acquity; column: Thermo Hypersil GOLD 1.9.mu., 50 mm.times.1 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min
10% A.fwdarw.2.2 min 10% A; oven: 50.degree. C.; flow rate: 0.33
ml/min; UV detection: 210 nm.
Starting Materials and Intermediates:
Example 1A
tert-Butyl (2E,6R)-6-hydroxyhept-2-enoate
##STR00052##
[0408] Solution A: 10.71 g (267.7 mmol) of 60% sodium hydride are
suspended in 150 ml of abs. THF, and 43.3 ml (276.7 mmol) of
tert-butyl P,P-dimethylphosphonoacetate are added dropwise with
cooling. The mixture is stirred at RT, and after about 30 min a
solution is formed.
[0409] 187.4 ml (187.4 mmol) of a 1 M solution of DIBAH in THF are
added dropwise to a solution, cooled to -78.degree. C., of 17.87 g
(178.5 mmol) of (R)-.gamma.-valerolactone
[(5R)-5-methyldihydrofuran-2(3H)-one] in 200 ml of abs. THF. The
solution is stirred at -78.degree. C. for 1 h, and solution A,
prepared above, is then added. After the end of the addition, the
mixture is slowly warmed to RT and stirred at RT overnight. The
reaction mixture is added to 300 ml of ethyl acetate and extracted
by stirring with 50 ml of concentrated potassium sodium tartrate
solution. After phase separation, the aqueous phase is re-extracted
with ethyl acetate. The organic phases are combined, washed with
sat. sodium chloride solution, dried over magnesium sulfate and
concentrated under reduced pressure. The residue is purified by
chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 5:1). This gives 32.2 g (90.1% of theory) of the target
product which contains small amount of the cis-isomer.
[0410] MS (DCI): m/z=218 (M+NH.sub.4).sup.+
[0411] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=6.70 (dt, 1H),
5.73 (d, 1H), 4.44 (d, 1H), 3.58 (m, 1H), 2.28-2.13 (m, 2H),
1.47-1.40 (m, 2H), 1.45 (s, 9H), 1.04 (d, 3H).
Example 2A
tert-Butyl (-)-6-hydroxyheptanoate
##STR00053##
[0413] 32.2 g (160.8 mmol) of tert-butyl
(2E,6R)-6-hydroxyhept-2-enoate are dissolved in 200 ml of ethanol,
and 1.7 g of 10% palladium on carbon are added. The mixture is
stirred at RT under an atmosphere of hydrogen (atmospheric
pressure) for 2 h and then filtered off through Celite. The
filtrate is concentrated under reduced pressure. The residue gives,
after chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 10:1.fwdarw.6:1), 15.66 g of the target product (48.1% of
theory).
[0414] MS (DCI): m/z=220 (M+NH.sub.4).sup.+
[0415] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=3.85-3.75 (m,
1H), 2.22 (t, 2H), 1.68-1.54 (m, 2H), 1.53-1.30 (m, 4H), 1.45 (s,
9H), 1.18 (d, 3H).
[0416] [.alpha.].sub.D.sup.20=-21.degree., c=0.118, chloroform.
Example 3A
Methyl 6-[(6-phenylthieno[2,3-d]pyrimidin-4-yl)amino]hexanoate
##STR00054##
[0418] Under an atmosphere of argon, 500 mg (2.03 mmol) of
4-chloro-6-phenylthieno[2,3-d]pyrimidine are initially charged in 2
ml of DMF, and 1.8 ml (1309 mg, 10.13 mmol) of DIEA and 736 mg
(4.05 mmol) of methyl 6-aminohexanoate hydrochloride are added. The
reaction is stirred at a bath temperature of 120.degree. C. for 1.5
h. For work-up, water is added to the cooled reaction mixture and
the mixture is extracted three times with ethyl acetate. The
combined extracts are washed with sat. sodium chloride solution and
dried over magnesium sulfate, and the solvent is removed completely
on a rotary evaporator. The residue is then chromatographed on
silica gel (Biotage.RTM. cartridge) using a gradient of cyclohexane
and ethyl acetate (4:1.fwdarw.2:1). This gives 590 mg of the target
product (82% of theory).
[0419] LC-MS (method 1): R.sub.t=2.54 min; m/z=356 (M+H).sup.+.
Example 4A
Methyl
6-[(5-bromo-6-phenylthieno[2,3-d]pyrimidin-4-yl)amino]hexanoate
##STR00055##
[0421] 544 mg (1.53 mmol) of methyl
6-[(6-phenylthieno[2,3-d]pyrimidin-4-yl)amino]-hexanoate are
suspended in 1.6 ml of acetonitrile, and 300 mg (1.68 mmol) of
N-bromosuccinimide are then added. The reaction mixture is then
stirred at RT for 1 h. Dichloromethane is added to the suspension,
the mixture is washed successively with sat. sodium bicarbonate
solution and sat. sodium chloride solution and the organic phase is
dried over sodium sulfate and concentrated under reduced pressure.
The residue is chromatographed on silica gel using a gradient of
cyclohexane and ethyl acetate (5:1.fwdarw.4:1). This gives 563 mg
of the target product (84% of theory).
[0422] LC-MS (method 1): R.sub.t=3.01 min; m/z=434 (M+H).sup.+
[0423] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.42 (s, 1H),
7.70-7.62 (m, 2H), 7.60-7.49 (m, 3H), 7.37 (t, 1H), 3.63-3.53 (m,
5H), 2.31 (t, 2H), 1.70-1.53 (m, 4H), 0.91-0.76 (m, 2H).
Example 5A
tert-Butyl
(6R)-6-[(6-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]heptanoate
##STR00056##
[0425] Under an atmosphere of argon, 500 mg (2.03 mmol) of
4-chloro-6-phenylthieno[2,3-d]pyrimidine and 615 mg (3.04 mmol) of
tert-butyl (-)-6-hydroxyheptanoate are initially charged in 3.4 ml
of THF and cooled to -20.degree. C., and 2.6 ml (1670 mg, 2.64
mmol) of a 1 M solution of
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)-phosphoranylidene]phosp-
horimidetriamide in hexane are added. The mixture is stirred at
-20.degree. C. for 30 min and then slowly warmed to 0.degree. C.
and stirred at this temperature for 1 h. For work-up, water is
added and the reaction mixture is neutralized with 1 M hydrochloric
acid and repeatedly extracted with dichloromethane. The combined
extracts are dried over sodium sulfate and concentrated under
reduced pressure. The residue is chromatographed on silica gel
(Biotage.RTM. cartridge) using a mobile phase gradient of
cyclohexane and ethyl acetate (30:1.fwdarw.20:1.fwdarw.10:1). This
gives 249 mg of the target product (30% of theory).
[0426] LC-MS (method 2): R.sub.t=5.01 min; m/z=413 (M+H).sup.+
[0427] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.64 (s, 1H),
7.86 (d, 2H), 7.79 (s, 1H), 7.50 (t, 1H), 7.46-7.41 (m, 1H), 5.50
(m, 1H), 2.19 (t, 2H), 1.88-1.66 (m, 2H), 1.60-1.29 (m, 14H), 1.39
(d, 3H), 1.32 (s, 9H).
[0428] [.alpha.].sub.D.sup.20=-71.degree., c=0.480, chloroform.
Example 6A
tert-Butyl
(6R)-6-[(5-bromo-6-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]heptan-
oate
##STR00057##
[0430] 215 mg (0.52 mmol) of tert-butyl
(6R)-6-[(6-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]heptanoate are
reacted with 102 mg (0.57 mmol) of N-bromosuccinimide in 0.6 ml of
acetonitrile at RT for 2 h. Dichloromethane is then added to the
suspension, the mixture is washed successively with sat. sodium
bicarbonate solution and sat. sodium chloride solution and the
organic phase is dried over sodium sulfate and concentrated under
reduced pressure. The residue is chromatographed on silica gel 60
using a mobile phase of cyclohexane and ethyl acetate (10:1). This
gives 214 mg of the target product (84% of theory).
[0431] LC-MS (method 3): R.sub.t=5.04 min; m/z=491 (M+H).sup.+
[0432] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.72 (s, 1H),
7.69 (dd, 2H), 7.61-7.49 (m, 3H), 5.51 (m, 1H), 2.19 (t, 2H),
1.90-1.65 (m, 2H), 1.61-1.28 (m, 14H), 1.39 (d, 3H), 1.32 (s,
9H).
Example 7A
2-Amino-1-benzyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-3-carbonitrile
and
2-amino-1-benzyl-5-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-3-carbonitri-
le (isomer mixture)
##STR00058##
[0434] 30.0 g (123.83 mmol) of
2-hydroxy-1-(4-methoxyphenyl)-2-phenylethanone are dissolved in 100
ml of toluene, and 13.5 ml (123.83 mmol) of benzylamine and 2.3 g
(12.38 mmol) of p-toluenesulfonic acid monohydrate are added. On a
water separator, the reaction mixture is stirred at boiling point
for 2 h. 8.2 g (123.83 mmol) of malononitrile are then suspended in
a little toluene and added dropwise continuously to the reaction
mixture, which is boiling gently. The mixture is then stirred at
boiling point for another 2 h. For work-up, the solvent is removed
completely on a rotary evaporator, the residue is recrystallized
from ethanol and the crystals are filtered off and dried under
reduced pressure. This gives 15.3 g (33% of theory) of the target
product as a mixture of regioisomers.
[0435] LC-MS (method 3): R.sub.t=3.81 min; m/z=380 (M+H).sup.+
[0436] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. (for both
isomers)=7.31-7.17 (m, 5H), 7.13 (d, 2H), 7.09-6.95 (m, 3H),
6.40-6.25 (m, 2H), 6.12 and 6.10 (2s, 2H), 4.96 and 4.93 (2s, 2H),
3.71 and 3.69 (2s, 3H).
Example 8A
7-Benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine
and
7-benzyl-6-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-a-
mine (isomer mixture)
##STR00059##
[0438] 15.2 g (40.06 mmol) of the mixture of
2-amino-1-benzyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-3-carbonitrile
and
2-amino-1-benzyl-5-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-3-carbonitri-
le are dissolved in a mixture of 60 ml of formamide, 20 ml of
dimethylformamide and 8 ml of 99% strength formic acid and stirred
under reflux at a bath temperature of about 190.degree. C. for 10
h. For work-up, the reaction mixture is cooled to RT, the
precipitated solid is filtered off and the filter residue is washed
with 5% strength aqueous sodium hydroxide solution. The filter
residue is recrystallized from ethanol and the crystals are once
more filtered off (and then discarded). The filtrate from the
recrystallization is evaporated to dryness on a rotary evaporator
and the residue is dried under reduced pressure. This gives 12.6 g
(45% of theory) of the target product as a mixture of
regioisomers.
[0439] LC-MS (method 2): R.sub.t=3.05 and 3.09 min; m/z in each
case=407 (M+H).sup.+
[0440] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. (for both
isomers)=8.17 and 8.19 (2s, 1H), 7.38-7.13 (m, 7H), 7.09 (d, 2H),
6.93-6.81 (m, 4H), 5.88 (br. s, 2H), 5.31 (s, 2H), 3.74 and 3.72
(2s, 3H).
Example 9A
7-Benzyl-4-chloro-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine
and
7-benzyl-4-chloro-6-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrim-
idine (isomer mixture)
##STR00060##
[0442] 12.6 g (31.02 mmol) of the mixture of
7-benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine
and
7-benzyl-6-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-a-
mine are initially charged in 13.5 ml of chloroform, and 11.6 ml
(1.7 g, 46.53 mmol) of a 4 M solution of hydrogen chloride in
dioxane and 8.3 ml (7.3 g, 62.04 mmol) of isoamyl nitrite are added
in succession. The reaction mixture is then stirred under reflux
for 2.5 h. For work-up, the mixture is diluted with chloroform and
then washed carefully with sat. sodium bicarbonate solution and
sat. sodium chloride solution. The organic phase is dried over
sodium sulfate and concentrated under reduced pressure. The crude
product is chromatographed on silica gel (Biotage.RTM. cartridge)
using a mobile phase of cyclohexane and ethyl acetate (20:1). This
gives 2.4 g (18% of theory) of the target product as a mixture of
regioisomers.
[0443] LC-MS (method 2): R.sub.t=4.40 min; m/z=426 (M+H).sup.+
[0444] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 6 (for both
isomers)=8.71 and 8.69 (2s, 1H), 7.40-7.12 (m, 10H), 6.92-6.79 (m,
4H), 5.45 (s, 2H), 3.74 and 3.72 (2s, 3H).
Example 10A
tert-Butyl
(6R)-6-{[7-benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-yl]oxy}heptanoate
##STR00061##
[0446] Under an atmosphere of argon, 800 mg (1.88 mmol) of the
mixture of
7-benzyl-4-chloro-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
e and
7-benzyl-4-chloro-6-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyri-
midine and 570 mg (2.82 mmol) of tert-butyl (-)-6-hydroxyheptanoate
are dissolved in 3.2 ml of THF, and 2.8 ml (1785 mg, 2.64 mmol) of
a 1 M solution of
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosph-
orimidetriamide in hexane are added dropwise at 0.degree. C. The
reaction mixture is kept at 0.degree. C. for 10 min and then warmed
to RT and stirred at this temperature for another 1 h. For work-up,
water is added and the mixture is neutralized with 1 M hydrochloric
acid and extracted repeatedly with dichloromethane. The combined
extracts are dried over sodium sulfate and concentrated under
reduced pressure. The residue is pre-purified on silica gel
(Biotage.RTM. cartridge) using a mobile phase of cyclohexane and
ethyl acetate (10:1). The isomers are then separated by preparative
RP-HPLC (column material: Phenomenex Gemini C18, 5 .mu.m) over a
running time of 30 min using a mobile phase of water and
acetonitrile (20:80). This gives 234 mg (21% of theory) of the
target product as a pure regioisomer.
[0447] LC-MS (method 2): R.sub.t=5.12 min; m/z=592 (M+H).sup.+
[0448] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.43 (s, 1H),
7.41-7.30 (m, 3H), 7.22-7.11 (m, 7H), 6.83 (m, 2H), 6.75 (d, 2H),
5.41-5.31 (m, 1H), 5.38 (s, 2H), 3.69 (s, 3H), 2.10 (t, 2H), 1.53
(m, 2H), 1.42 (m, 2H), 1.34 (s, 9H), 1.28-1.12 (m, 2H), 1.25 (d,
3H).
[0449] [.alpha.].sub.D.sup.20=-48.degree., c=0.470, chloroform.
Example 11A
(6R)-6-{[7-Benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-yl]oxy}heptanoic acid
##STR00062##
[0451] 130 mg (0.22 mmol) of tert-butyl
(6R)-6-{[7-benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]oxy}heptanoate are dissolved in 0.7 ml of dichloromethane,
0.2 ml of trifluoroacetic acid is added and the mixture is stirred
at RT for 40 min. For work-up, the solvent is removed completely on
a rotary evaporator and the residue is purified by preparative
RP-HPLC. This gives 93 mg (79% of theory) of the target
product.
[0452] LC-MS (method 4): R.sub.t=2.68 min; m/z=536 (M+H).sup.+
[0453] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=12.00 (br. s,
1H), 8.44 (s, 1H), 7.41-7.29 (m, 3H), 7.24-7.10 (m, 7H), 6.83 (dd,
2H), 6.75 (d, 2H), 5.41-5.29 (m, 1H), 5.38 (s, 2H), 3.69 (s, 3H),
2.11 (t, 2H), 1.53 (m, 2H), 1.42 (m, 2H), 1.32-1.13 (m, 2H), 1.25
(d, 3H).
[0454] [.alpha.].sub.D.sup.20=-45.degree., c=0.490, chloroform.
Example 12A
2-Phenyl-6,7-dihydro-1-benzofuran-4(5H)-one
##STR00063##
[0456] Under an atmosphere of argon, 107.6 g (196.20 mmol) of
ammonium cerium(IV) nitrate and 37.5 g (445.91 mmol) of sodium
bicarbonate are initially charged in 130 ml of acetonitrile. The
suspension is cooled to 0.degree. C. A solution of 10.0 g (89.18
mmol) of 1,3-cyclohexanedione and 27.3 g (267.55 mmol) of
phenylacetylene in 20 ml of acetonitrile is added dropwise, and the
mixture is stirred at RT for 3 h. For work-up, the solid is
filtered off, the filter residue is washed with acetonitrile and
the filtrate is concentrated under reduced pressure. The residue is
taken up in ethyl acetate and washed successively with water, sat.
sodium bicarbonate solution and sat. sodium chloride solution, and
the organic phase is dried over magnesium sulfate. The solvent is
removed completely on a rotary evaporator and the resulting brown
oil is chromatographed on silica gel using a gradient of
cyclohexane and ethyl acetate
(20:1.fwdarw.10:1.fwdarw.8:1.fwdarw.6:1). This gives 6.9 g (36% of
theory) of the target product.
[0457] LC-MS (method 2): R.sub.t=3.43 min; m/z=213 (M+H).sup.+
[0458] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.74 (d, 2H),
7.44 (t, 2H), 7.34 (t, 1H), 7.18 (s, 1H), 2.97 (t, 2H), 2.45 (t,
2H), 2.12 (m, 2H).
Example 13A
3-Bromo-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one
##STR00064##
[0460] Under an atmosphere of argon, 6.9 g (32.42 mmol) of
2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one are suspended in 34.4
ml of acetonitrile, 6.9 g (38.90 mmol) of N-bromosuccinimide are
added and the mixture is stirred at RT for 20 min. The mixture is
then concentrated under reduced pressure, the residue is taken up
in dichloromethane, the insoluble residue is filtered off and the
filter residue is washed with dichloromethane. The combined
filtrates are concentrated under reduced pressure and the residue
is chromatographed on silica gel (Biotage.RTM. cartridge) using a
mobile phase of dichloromethane and cyclohexane (30:1). This gives
7.6 g (80% of theory) of the target product.
[0461] LC-MS (method 3): R.sub.t=3.56 min; m/z=291 (M+H).sup.+
[0462] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.91 (d, 2H),
7.53 (t, 2H), 7.43 (t, 1H), 2.99 (t, 2H), 2.47 (t, 2H), 2.12 (m,
2H).
Example 14A
3-(4-Methoxyphenyl)-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one
##STR00065##
[0464] Under an atmosphere of argon, 6.8 g (23.18 mmol) of
3-bromo-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one are dissolved
in 22.5 ml of DMF, and 0.8 g (1.16 mmol) of
bis(triphenylphosphine)palladium(II) chloride, 23.2 ml (4.9 g,
46.36 mmol) of 2 M aqueous sodium carbonate solution and 3.9 g
(25.5 mmol) of 4-methoxyphenylboronic acid are added. The reaction
mixture is stirred at 80.degree. C. for 5 h. For work-up,
dichloromethane is added to the cooled reaction mixture, the
catalyst is filtered off through kieselguhr, the filter residue is
washed with dichloromethane and the filtrate is concentrated under
reduced pressure. The residue is chromatographed on silica gel
using a gradient of cyclohexane and ethyl acetate
(10:1.fwdarw.5:1). This gives 5.0 g (67% of theory) of the target
product.
[0465] LC-MS (method 2): R.sub.t=4.04 min; m/z=319 (M+H).sup.+
[0466] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.35-7.18 (m,
5H), 7.21 (d, 2H), 6.93 (d, 2H), 3.79 (s, 3H), 2.99 (t, 2H), 2.43
(t, 2H), 2.13 (m, 2H).
Example 15A
5-Bromo-3-(4-methoxyphenyl)-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one
##STR00066##
[0468] Under an atmosphere of argon, 500 mg (1.57 mmol) of
3-(4-methoxyphenyl)-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one are
dissolved in 3 ml of THF, and 590 mg (1.57 mmol) of
phenyltrimethylammonium tribromide are added. The reaction mixture
is stirred at RT for 6 h. For work-up, the solution is concentrated
under reduced pressure and the residue is purified by preparative
RP-HPLC using a gradient of water and acetonitrile. This gives 550
mg (88% of theory) of the target product.
[0469] LC-MS (method 5): R.sub.t=2.49 min; m/z=397 (M+H).sup.+
[0470] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.39-7.26 (m,
5H), 7.21 (d, 2H), 6.96 (d, 2H), 4.80 (t, 1H), 3.80 (s, 3H), 3.09
(m, 2H), 2.75-2.63 (m, 1H), 2.58-2.40 (m, 1H).
Example 16A
3-(4-Methoxyphenyl)-2-phenyl-1-benzofuran-4-ol
##STR00067##
[0472] Under an atmosphere of argon, 1.0 g (2.52 mmol) of
5-bromo-3-(4-methoxyphenyl)-2-phenyl-6,7-dihydro-1-benzofuran-4(5H)-one
are suspended in 20 ml of methanol, and 0.7 ml (0.5 g, 5.03 mmol)
of triethylamine is added. After 4 h of stirring under reflux,
another 0.7 ml (0.5 g, 5.03 mmol) of triethylamine is added and the
mixture is stirred at boiling point overnight. The cooled reaction
solution is poured into 1 N hydrochloric acid and extracted three
times with ethyl acetate, and the combined extracts are washed with
sat. sodium bicarbonate solution and sat. sodium chloride solution,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue is chromatographed on silica gel
(Biotage.RTM. cartridge) using a mobile phase of cyclohexane and
ethyl acetate (10:1). The concentrated product fraction is
triturated with a little methanol and the resulting crystals are
filtered off and dried under reduced pressure. This gives 0.1 g
(15% of theory) of the target product.
[0473] LC-MS (method 4): R.sub.t=2.59 min; m/z=317 (M+H).sup.+
[0474] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=9.60 (s, 1H),
7.43 (d, 2H), 7.38-7.25 (m, 5H), 7.15 (t, 1H), 7.08 (d, 1H), 6.98
(d, 2H), 6.61 (d, 1H), 3.81 (s, 3H).
Example 17A
tert-Butyl (+)-(6S)-6-bromoheptanoate
##STR00068##
[0476] At 0.degree. C., a solution of 2.3 g (5.4 mmol) of
triphenylphosphine dibromide in 15 ml of abs. toluene is added
dropwise to a solution of 1.0 g (4.9 mmol) of tert-butyl
(-)-6-hydroxyheptanoate in 10 ml of abs. dichloromethane over a
period of 1-2 h. After the end of the addition, the mixture is
stirred at 0.degree. C. for about 90 min. The resulting suspension
is filtered through Celite and the filter residue is washed
thoroughly with dichloromethane. The filtrate is washed with water,
dried over sodium sulfate and concentrated under reduced pressure.
The residue is chromatographed on silica gel (Biotage.RTM.
cartridge, mobile phase cyclohexane/ethyl acetate 40:1). This gives
880.7 mg (67.2% of theory) of the target product.
[0477] GC-MS (method 6): R.sub.t=4.48 min;
[0478] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=4.28 (m, 1H),
2.19 (t, 2H), 1.80-1.71 (m, 2H), 1.67 (d, 3H), 1.55-1.35 (m, 6H),
1.40 (5, 9H).
[0479] [.alpha.].sub.D.sup.20=+30.degree., c=0.55, chloroform.
Example 18A
4-Bromo-5-phenyl-2-furaldehyde
##STR00069##
[0481] Under an atmosphere of argon, 17.1 g (95.83 mmol) of
N-bromosuccinimide are added to 15.0 g (87.12 mmol) of
5-phenylfurfural suspended in 90 ml of acetonitrile. The reaction
mixture is stirred at RT overnight. The mixture is then
concentrated under reduced pressure, and the residue is
chromatographed on silica gel using a mobile phase of cyclohexane
and ethyl acetate (30:1). This gives 16.3 g (75% of theory) of the
target product.
[0482] LC-MS (method 1): R.sub.t=2.55 min; m/z=250 (M+H).sup.+
[0483] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=9.61 (s, 1H),
8.02 (dd, 2H), 7.87 (s, 1H), 7.63-7.50 (m, 3H).
Example 19A
4-(4-Methoxyphenyl)-5-phenyl-2-furaldehyde
##STR00070##
[0485] Under an atmosphere of argon, 1.1 g (1.62 mmol) of
bis(triphenylphosphine)-palladium(II) chloride, 64.9 ml (13.76 g,
129.84 mmol) of 2 M aqueous sodium carbonate solution and 10.9 g
(71.41 mmol) of 4-methoxyphenylboronic acid are added to 16.3 g
(64.92 mmol) of 4-bromo-5-phenyl-2-furaldehyde dissolved in 90 ml
of DMF. The reaction mixture is stirred at 80.degree. C. for 2 h.
For work-up, water is added to the cooled mixture and the mixture
is extracted three times with dichloromethane. The combined
extracts are dried over magnesium sulfate and concentrated under
reduced pressure. The residue is chromatographed on silica gel
using a mobile phase of cyclohexane and ethyl acetate (20:1). This
gives 14.5 g (80% of theory) of the target product.
[0486] LC-MS (method 1): R.sub.t=2.76 min; m/z=279 (M+H).sup.+
[0487] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=9.64 (s, 1H),
7.74 (s, 1H), 7.55 (dd, 2H), 7.48-7.39 (m, 3H), 7.35 (d, 2H), 7.00
(d, 2H), 3.80 (s, 3H).
Example 20A
(2E)-3-[4-(4-Methoxyphenyl)-5-phenyl-2-furyl]acrylic acid
##STR00071##
[0489] Under an atmosphere of argon, 5.0 g (17.97 mmol) of
4-(4-methoxyphenyl)-5-phenyl-2-furaldehyde and 1.9 g (17.97 mmol)
of malonic acid are suspended in 9 ml of pyridine. After 1 h of
stirring at 100.degree. C., another 0.5 g (4.49 mmol) of malonic
acid are added, and the mixture is stirred at 100.degree. C. for a
further 8 h. The cooled reaction solution is then poured into a
mixture of ice-water and hydrochloric acid. Overnight, crystals
precipitate from the acidified solution. The solid is filtered off,
washed with water until neutral, dried under reduced pressure and
chromatographed on silica gel using a gradient of dichloromethane
and methanol (100:1.fwdarw.50:1.fwdarw.20:1.fwdarw.10:1). This
gives 2.0 g (35% of theory) of the target product.
[0490] LC-MS (method 5): R.sub.t=2.17 min; m/z=321 (M+H).sup.+
[0491] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=12.43 (s, 1H),
7.55 (dd, 2H), 7.48-7.25 (m, 6H), 7.14 (s, 1H), 7.00 (d, 2H), 6.35
(d, 1H), 3.78 (s, 3H).
Example 21A
(2E)-3-[4-(4-Methoxyphenyl)-5-phenyl-2-furyl]acrylic acid azide
##STR00072##
[0493] Under an atmosphere of argon, 8.2 g (25.66 mmol) of
(2E)-3-[4-(4-methoxyphenyl)-5-phenyl-2-furyl]acrylic acid are
suspended in 30 ml of acetone, 4.1 ml (29.77 mmol) of triethylamine
and a further 30 ml of acetone are added and the mixture is cooled
to -10.degree. C. 3.1 ml (32.07 mmol) of ethyl chloroformate,
dissolved in 6 ml of acetone, are added dropwise, and the mixture
is stirred at 0.degree. C. for 30 min. 2.5 g (38.49 mmol) of sodium
azide, dissolved in 16 ml of water, are then added to the reaction
mixture at 0.degree. C., and the mixture is diluted with 10 ml of
acetone. The mixture is warmed to RT and stirred for another 1 h.
For work-up, the suspension is diluted with water, the precipitate
is filtered off, the filter residue is washed with water until
neutral and the solid is dried under reduced pressure. This gives
8.4 g (95% of theory) of the target product.
[0494] LC-MS (method 7): R.sub.t=6.72 min; m/z=318
(M+H-N.sub.2).sup.+
[0495] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.65-7.55 (m,
3H), 7.44-7.27 (m, 6H), 7.01 (d, 2H), 6.45 (d, 1H), 3.79 (s,
3H).
Example 22A
3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4(5H)-one
##STR00073##
[0497] 8.4 g (6.37 mmol) of
(2E)-3-[4-(4-methoxyphenyl)-5-phenyl-2-furyl]acrylic acid azide are
dissolved in 10.5 ml of toluene, 7.6 ml (5.9 g, 31.77 mmol) of
tri-n-butylamine and 21.1 ml of Dowtherm A are added and the
mixture is stirred under a strong stream of argon at a bath
temperature of 230.degree. C. for 2 h. The reaction mixture is then
cooled in an ice-bath, resulting in the precipitation of crystals.
The suspension is diluted with diethyl ether, the solid is filtered
off and washed with diethyl ether and the product is dried under
reduced pressure. This gives 5.1 g (65% of theory) of the target
product.
[0498] LC-MS (method 5): R.sub.t=1.90 min; m/z=318 (M+H).sup.+
[0499] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=11.42 (d, 1H),
7.43 (d, 2H), 7.38-7.25 (m, 6H), 6.97 (d, 2H), 6.69 (d, 1H), 3.81
(s, 3H).
Example 23A
4-Chloro-3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridine
##STR00074##
[0501] Under an atmosphere of argon, 5.1 g (15.91 mmol) of
3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4(5H)-one are
stirred in 30 ml (318 mmol) of phosphorus oxychloride at
130.degree. C. for 10 h. The cooled reaction mixture is then
diluted with ethyl acetate, ice-water is added carefully and the pH
is adjusted to 6-7 using a mixture of sat. sodium carbonate
solution and 10% strength aqueous sodium hydroxide solution. The
organic phase is separated off, the aqueous phase is extracted
twice with ethyl acetate and the combined extracts are dried over
magnesium sulfate and concentrated under reduced pressure. The
residue is triturated with methanol and the crystals are filtered
off, washed with methanol and dried under reduced pressure. This
gives 4.9 g (92% of theory) of the target product.
[0502] LC-MS (method 4): R.sub.t=2.66 min; m/z=336 (M+H).sup.+
[0503] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.33 (d, 1H),
7.85 (d, 1H), 7.52 (dd, 2H), 7.45-7.25 (m, 5H), 7.08 (d, 2H), 3.83
(s, 3H).
Example 24A
3-{[3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-2,2-dimethy-
lpropan-1-ol
##STR00075##
[0505] Under an atmosphere of argon, 200 mg (0.60 mmol) of
4-chloro-3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridine and 123 mg
(1.19 mmol) of 3-amino-2,2-dimethyl-1-propanol are dissolved in 0.5
ml of DMF, 0.2 ml (1.19 mmol) of diisopropylethylamine are added
and the mixture is stirred at 120.degree. C. for 2 days. Water is
added to the cooled reaction mixture, and the mixture is saturated
with sodium chloride and extracted three times with ethyl acetate.
The combined extracts are dried over magnesium sulfate and
concentrated under reduced pressure. The residue is chromatographed
on silica gel (Biotage.RTM. cartridge) using a gradient of
cyclohexane and ethyl acetate
(10:1.fwdarw.5:1.fwdarw.3:1.fwdarw.2:1). This gives 56 mg (23% of
theory) of the target product.
[0506] LC-MS (method 1): R.sub.t=1.86 min; m/z=403 (M+H).sup.+
[0507] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.88 (d, 1H),
7.52-7.40 (m, 4H), 7.38-7.25 (m, 3H), 7.15 (d, 2H), 6.95 (d, 1H),
4.63 (t, 1H), 4.50 (t, 1H), 3.85 (s, 3H), 3.15 (d, 2H), 2.95 (d,
2H), 0.61 (s, 6H).
Example 25A
tert-Butyl 6-{[(benzyloxy)carbonyl]amino}hexanoate
##STR00076##
[0509] 10.0 g (37.69 mmol) of
6-{[(benzyloxy)carbonyl]amino}hexanoic acid are suspended in a
mixture of 21 ml of dichloromethane and 99 ml of cyclohexane. 9.8 g
(45.23 mmol) of tert-butyl 2,2,2-trichloroacetimidate are added,
0.3 ml (566 mg, 3.77 mmol) of trifluoromethanesulfonic acid is
added dropwise at 0-10.degree. C. and the mixture is stirred at RT
overnight. The solid formed is filtered off, the filter residue is
washed with dichloromethane and the filtrate is concentrated under
reduced pressure. The residue is chromatographed on silica gel 60
using a mobile phase of cyclohexane and ethyl acetate (5:1). This
gives 4.9 g (40% of theory) of the target compound.
[0510] LC-MS (method 2): R.sub.t=3.91 min; m/z=322 (M+H).sup.+
[0511] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.39-7.25 (m,
5H), 7.22 (t, 1H), 4.99 (s, 2H), 2.97 (q, 2H), 2.15 (t, 2H), 1.48
(m, 2H), 1.43-1.33 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Example 26A
tert-Butyl 6-aminohexanoate
##STR00077##
[0513] 4.9 g (15.21 mmol) of tert-butyl
6-{[(benzyloxy)carbonyl]amino}hexanoate are initially charged in a
mixture of 15 ml of ethanol and 1.5 ml of THF, 0.3 g (0.15 mmol) of
5% palladium on carbon are added and the mixture is hydrogenated at
atmospheric pressure and RT for 4 h. The catalyst is filtered off
through Celite, the filter residue is washed with ethanol/THF
(10:1), the filtrate is concentrated under reduced pressure and the
residue is dried under reduced pressure. This gives 2.8 g (97% of
theory) of the target product.
[0514] LC-MS (method 8): R.sub.t=2.41 min; m/z=188 (M+H).sup.+
[0515] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=2.21-2.12 (m,
2H), 1.55-1.15 (m, 4H), 1.39 (s, 9H).
Example 27A
1-Benzyl-4-(benzyloxy)pyridin-2(1H)-one
##STR00078##
[0517] 9.0 g (44.73 mmol) of 4-(benzyloxy)pyridin-2(1H)-one are,
together with 8.94 g (223.63 mmol) of powdered sodium hydroxide and
6.074 g (17.89 mmol) of tetra-n-butylammonium hydrogensulfate,
initially charged in 1.6 liter of toluene. 38.25 g (223.63 mmol) of
benzyl bromide are added, and the mixture is heated at 80.degree.
C. with stirring for 2 hours. The mixture is then concentrated and
the residue is dissolved in a mixture of 500 ml each of water and
dichloromethane. The phases are separated and the aqueous phase is
extracted once with 200 ml of dichloromethane. The combined
dichloromethane phases are washed once with 100 ml of water and
once with 100 ml of saturated sodium chloride solution. The
dichloromethane phases are dried over magnesium sulfate and
concentrated. The residue obtained is triturated with petroleum
ether and the solid is filtered off with suction. The product is
dried under high vacuum, giving 13.0 g (99.8% of theory) of the
target compound.
[0518] LC-MS (method 3): R.sub.t=3.21 min; m/z=292 (M+H).sup.+
[0519] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.69 (d, 1H),
7.45-7.22 (m, 10H), 6.02 (dd, 1H), 5.94 (d, 1H), 5.08 (s, 2H), 5.02
(s, 2H).
Example 28A
1-Benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one
##STR00079##
[0521] 14.50 g (49.77 mmol) of
1-benzyl-4-(benzyloxy)pyridin-2(1H)-one are dissolved in 1 liter of
acetonitrile. 20.16 g (89.58 mmol) of 1-iodopyrrolidine-2,5-dione
are added, the reaction flask is wrapped in aluminum foil and the
mixture is stirred at room temperature for 20 h. The mixture is
then concentrated and the residue is purified by column
chromatography on silica gel using a cyclohexane/ethyl acetate
gradient (9:1.fwdarw.8:2.fwdarw.7:3.fwdarw.6:4.fwdarw.1:1). The
product-containing fractions are concentrated and the residue is
stirred at 50.degree. C. with 250 ml of a cyclohexane/ethyl acetate
mixture. The mixture is then once more cooled to 0.degree. C., and
the solid formed is filtered off with suction. In this manner, 15.5
g (74.6% of theory) of the target compound are obtained.
[0522] LC-MS (method 9): R.sub.t=2.47 min; m/z=418 (M+H).sup.+
[0523] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.92 (d, 1H),
7.48-7.38 (m, 4H), 7.37-7.24 (m, 6H), 6.39 (d, 1H), 5.31 (s, 2H),
5.12 (s, 2H).
Example 29A
7-Benzyl-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4(7H)-one
##STR00080##
[0525] 13.20 g (31.64 mmol) of
1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one are, together with
26.4 ml of triethylamine, initially charged in 224 ml of
acetonitrile. 1.11 g (1.58 mmol) of
bis(triphenylphosphine)palladium(II) chloride, 301 mg (1.58 mmol)
of copper(I) iodide and 4.20 g (41.13 mmol) of ethynylbenzene are
added, and the mixture is, under argon and with stirring, heated at
60.degree. C. for 22 h. The mixture is then allowed to cool to room
temperature, 11.01 g (47.45 mmol) of 4-ethyliodobenzene are added
and the mixture is once more, under argon and with stirring, heated
at 60.degree. C. for 24 h. The mixture is then concentrated and
filtered through silica gel (mobile phase: cyclohexane/ethyl
acetate 1:1, then dichloromethane/methanol 95:5). The
product-containing fractions are combined and concentrated. The
product obtained in this manner is once more purified by column
chromatography on silica gel (mobile phase:
dichloromethane/methanol 100:3). The product-containing fractions
are once more combined and concentrated. The residue is dissolved
in warm ethyl acetate, a little activated carbon is added, the
mixture is briefly heated to the boil and the activated carbon is
filtered off again. After cooling to room temperature, the
precipitated crystals are filtered off with suction, and more
crystals are obtained from the mother liquor. In this manner, a
total of 6.00 g (44.1% of theory) of the target compound are
obtained.
[0526] LC-MS (method 1): R.sub.t=2.86 min; m/z=406 (M+H).sup.+
[0527] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.85 (d, 1H),
7.49-7.23 (m, 11H), 7.22 (d, 2H), 6.05 (d, 1H), 5.45 (s, 2H),
2.69-2.61 (q, 2H), 1.26-1.21 (t, 3H).
Example 30A
4-Chloro-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine
##STR00081##
[0529] 6.00 g (14.8 mmol) of
7-benzyl-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4(7H)-one are
initially charged in 150 ml of chloroform. At room temperature, 0.5
ml of DMF and then, slowly, 7.51 g (59.19 mmol) of oxalyl chloride
are added, and the mixture is then stirred under reflux for 18 h.
The mixture is then concentrated and the residue is purified by
chromatography on silica gel (mobile phase: cyclohexane/ethyl
acetate 85:15). This gives 3.22 g (65.2% of theory) of the target
compound.
[0530] LC-MS (method 1): R.sub.t=3.41 min; m/z=334 (M+H).sup.+
[0531] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=8.20 (d, 1H),
7.62-7.58 (m, 2H), 7.35 (d, 2H), 7.31-7.25 (m, 5H), 7.18 (d, 1H),
2.80-2.72 (q, 2H), 1.35-1.30 (t, 3H).
Example 31A
3-{[3-(4-Ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-2,2-dimethylp-
ropan-1-ol
##STR00082##
[0533] 400 mg (1.2 mmol) of
4-chloro-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine are, together
with 618 mg (5.99 mmol) of 1-amino-2,2-dimethyl-3-propanol,
dissolved in 4 ml of DMSO. The mixture is allowed to react in a
microwave initially at 150.degree. C. for 1 h and then at
200.degree. C. for a further 2 h. The mixture is then diluted with
300 ml of water and extracted twice with in each case 200 ml of
dichloromethane. The combined dichloromethane phases are dried over
magnesium sulfate and concentrated. The product is purified by
chromatography on silica gel (mobile phase: cyclohexane/ethyl
acetate 1:1), giving 250 mg (52.1% of theory) of the target
compound.
[0534] LC-MS (method 1): R.sub.t=2.80 min; m/z=401 (M+H).sup.+
[0535] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.97 (d, 1H),
7.56-7.52 (m, 2H), 7.42 (d, 2H), 7.35 (d, 2H), 7.26-7.21 (m, 3H),
6.28 (d, 1H), 4.42-4.38 (t, 1H), 3.16 (s, 2H), 2.93 (d, 2H),
2.78-2.71 (q, 2H), 1.32-1.28 (t, 3H), 0.68 (s, 6H).
Example 32A
2-{[3-(4-Ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}ethanol
##STR00083##
[0537] 150 mg (0.45 mmol) of
4-chloro-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine and 39 mg
(0.63 mmol) of 1,2-ethanediol are dissolved in 1 ml of DMF, and 23
mg (0.58 mmol) of 60% sodium hydride are added at 0.degree. C. The
suspension is stirred at RT for 3 h and a further 45 min at
60.degree. C. Separately, 39 mg (0.63 mmol) of 1,2-ethanediol and
23 mg (0.58 mmol) of 60% sodium hydride are then stirred at RT in
DMF for 30 min, the suspension is filtered, the filtrate is, at RT,
added dropwise to the above reaction solution, and the solution is
then once more stirred at 60.degree. C. overnight. This procedure
is repeated with a further 39 mg (0.63 mmol) of 1,2-ethanediol and
23 mg (0.58 mmol) of 60% sodium hydride, and the reaction mixture
is stirred at 60.degree. C. for another 3 h. Then, after cooling,
water is added, the mixture is extracted with ethyl acetate and the
organic phase is washed with sat. sodium chloride solution, dried
over magnesium sulfate and concentrated under reduced pressure. The
residue is chromatographed on silica gel 60 using a mobile phase of
dichloromethane and methanol (50:1). In this manner, 172 mg (27% of
theory) of the target product are obtained.
[0538] LC-MS (method 1): R.sub.t=2.79 min; m/z=360 (M+H).sup.+
[0539] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.20 (d, 1H),
7.52 (dd, 2H), 7.45-7.29 (m, 5H), 7.25 (d, 2H), 6.98 (d, 1H), 4.64
(t, 1H), 4.11 (t, 2H), 3.53 (q, 2H), 2.68 (q, 2H), 1.24 (t,
3H).
Example 33A
3-{[3-(4-Ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}propan-1-ol
##STR00084##
[0541] At 0.degree. C., 15.6 mg (0.389 mmol, 60%) of sodium hydride
are added to a solution of 100 mg (0.30 mmol) of
4-chloro-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine and 30 .mu.l
(0.419 mmol) of 1,3-propanediol in 1.0 ml of DMF. The mixture is
stirred initially at RT for 2 h and then at 60.degree. C.
overnight. After cooling, a further 1.4 eq. of 1,3-propanediol and
1.3 eq. 60% sodium hydride are added, and the reaction mixture is
once more heated at 80.degree. C. overnight. After cooling, the
reaction mixture is diluted with water and extracted with ethyl
acetate. The organic phase is dried over sodium sulfate and
concentrated under reduced pressure and the residue is dried under
high vacuum. Chromatography on silica gel (mobile phase:
dichloromethane/methanol 50:1) gives 70 mg (60.4% of theory) of the
target compound.
[0542] LC-MS (method 1): R.sub.t=2.80 min; m/z=374 (M+H).sup.+
[0543] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.19 (d, 1H),
7.53 (dd, 2H), 7.39-7.29 (m, 5H), 7.28 (d, 2H), 6.95 (d, 1H), 4.39
(t, 1H), 4.09 (t, 2H), 3.18 (q, 2H), 2.69 (q, 2H), 1.61 (m, 2H),
1.25 (t, 3H).
Example 34A
Methyl 3-nitrophenoxyacetate
##STR00085##
[0545] 50 g (359.4 mmol) of 3-nitrophenol and 175.67 g (539 mmol)
of cesium carbonate are initially charged in 1.0 liter of acetone,
and 71.5 g (467.3 mmol) of methyl bromoacetate are added. The
mixture is stirred at 50.degree. C. for 1 h and, after cooling,
poured into 7.5 liter of water. The suspension is stirred for 30
min and then filtered off with suction, and the filter residue is
washed with water. The solid is dried in a drying cabinet at
50.degree. C. and 100 mbar. This gives 64.3 g (84.7% of theory) of
the target compound.
[0546] MS (DCI): m/z=229 (M+NH.sub.4).sup.+
[0547] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=7.90 (dd, 1H),
7.43 (t, 1H), 7.48 (t, 1H), 7.28 (dd, 1H), 4.75 (s, 2H), 3.86 (s,
3H).
Example 35A
Methyl 3-aminophenoxyacetate
##STR00086##
[0549] Under argon, 1.3 g of palladium on activated carbon (10%)
are added to 13 g (61.6 mmol) of methyl 3-nitrophenoxyacetate in
150 ml of methanol. The mixture is stirred under an atmosphere of
hydrogen (atmospheric pressure) at RT for 18 h. The catalyst is
filtered off through kieselguhr and the filtrate is concentrated
under reduced pressure. This gives, after drying under high vacuum,
10.7 g (95.9% of theory) of the target compound.
[0550] MS (DCI): m/z=199 (M+NH.sub.4).sup.+, 182 (M+H).sup.+
[0551] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.10-7.02 (m,
1H), 6.35-6.23 (m, 2H), 4.58 (s, 2H), 3.79 (s, 3H), 3.65 (br. s,
2H).
Working Examples
General Procedure A
Palladium-Catalyzed Arylation of Heteroaryl Bromides
[0552] 10% by volume of methanol, the appropriate arylboronic acid
(1.2 to 1.8 eq.), potassium carbonate (1.5 to 2.0 eq.) and
bis(triphenylphosphine)palladium(II) chloride (0.04 to 0.1 eq.) are
added successively to a solution of the heteroaryl bromide in
question in DMSO (about 0.1 to 0.5 mol/l). Under argon, the
reaction mixture is stirred at 80-100.degree. C. for 2 to 8 h.
After cooling, the crude mixture is separated by preparative
RP-HPLC and the target product is isolated.
The Working Examples Below are Obtained According to General
Procedure A:
TABLE-US-00001 [0553] Example Structure Analytical data 1
##STR00087## LC-MS (method 2): R.sub.t = 4.16 min; m/z = 462 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 8.40 (s,
1H), 7.35 (d, 2H), 7.32- 7.22 (m, 5H), 7.07 (d, 2H), 4.84 (t, 1H),
3.82 (s, 3H), 3.58 (s, 3H), 3.27 (q, 2H), 2.23 (t, 2H), 1.41 (m,
2H), 1.32-1.20 (m, 2H), 1.07- 0.95 (m, 2H). 2 ##STR00088## LC-MS
(method 2): R.sub.t = 4.54 min; m/z = 460 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 8.41 (s, 1H), 7.36
(s, 4H), 7.32- 7.22 (m, 5H), 4.68 (t, 1H), 3.57 (s, 3H), 3.23 (q,
2H), 2.69 (q, 2H), 2.23 (t, 2H), 1.40 (m, 2H), 1.28-1.14 (m, 5H),
1.08-0.95 (m, 2H). 3 ##STR00089## LC-MS (method 3): R.sub.t = 4.98
min; m/z = 519 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. = 8.64 (s, 1H), 7.86-7.75 (m, 5H), 7.19 (d, 2H), 6.91 (d,
2H), 5.21 (m, 1H), 3.78 (s, 3H), 2.08 (t, 2H), 1.43-1.18 (m, 4H),
1.34 (s, 9H), 1.12 (d, 3H), 1.05-0.86 (m, 2H).
[.alpha.].sub.D.sup.20 = -60.degree., c = 0.475, chloroform. 4
##STR00090## LC-MS (method 3): R.sub.t = 5.28 min; m/z = 517 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 8.64 (s,
1H), 7.84-7.75 (m, 5H), 7.18 (m, 4H), 5.18 (m, 1H), 2.65 (q, 2H),
2.05 (t, 2H), 1.41-1.12 (m, 7H), 1.35 (s, 9H), 1.09 (d, 3H), 1.02-
0.90 (m, 2H). [.alpha.].sub.D.sup.20 = -54.degree., c = 0.455,
chloroform.
Example 5
(6R)-6-{[5-(4-Methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}-
heptanoic acid
##STR00091##
[0555] 92 mg (0.17 mmol) of
(6R)-6-{[7-benzyl-5-(4-methoxyphenyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]oxy}heptanoic acid are initially charged in a mixture of 30
ml of acetic acid and 3 ml of water, 10 mg of 10% palladium on
carbon are then added and the mixture is stirred in an atmosphere
of hydrogen at atmospheric pressure overnight. Two more times, in
each case 10 mg of catalyst are then added and the mixture is
hydrogenated at atmospheric pressure for a further 5 days. For
work-up, the catalyst is filtered off, the filter residue is washed
with acetic acid and the filtrate is concentrated under reduced
pressure at 10-20.degree. C. The residue is purified by preparative
RP-HPLC (gradient of water and acetonitrile). This gives 5 mg (7.0%
of theory) of the title compound.
[0556] LC-MS (method 1): R.sub.t=2.59 min; m/z=446 (M+H).sup.+
[0557] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=12.34 (s, 1H),
8.34 (s, 1H), 7.40 (d, 2H), 7.35-7.25 (m, 3H), 7.21 (d, 2H), 6.88
(d, 2H), 5.27 (m, 1H), 3.76 (s, 3H), 2.10 (t, 2H), 1.53-1.43 (m,
4H), 1.31-1.05 (m, 2H), 1.20 (d, 3H).
[0558] [.alpha.].sub.D.sup.20=-24.degree., c=0.050, chloroform.
General Procedure B
Hydrolysis of Methyl or Ethyl Esters to the Corresponding
Carboxylic Acids
[0559] At RT, 1.5 to 10 eq. of sodium hydroxide, as a 1 N aqueous
solution, are added to a solution of the methyl or ethyl ester in
THF or THF/methanol (1:1) (concentration about 0.05 to 0.5 mol/l).
The mixture is stirred at RT for a period of 0.5-18 h and then
neutralized or acidified slightly with 1 N hydrochloric acid. If a
solid precipitates out, the product can be isolated by filtration,
washing with water and drying under high vacuum. Alternatively, the
target compound is isolated directly from the crude product, if
appropriate after extractive work-up with dichloromethane, by
preparative RP-HPLC (mobile phase: water/acetonitrile
gradient).
The Working Examples Below are Obtained According to General
Procedure B:
TABLE-US-00002 [0560] Example Structure Analytical data 6
##STR00092## LC-MS (method 1): R.sub.t = 2.61 min; m/z = 448 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 8.38 (s,
1H), 7.35 (d, 2H), 7.32- 7.22 (m, 5H), 7.08 (d, 2H), 4.84 (t, 1H),
3.82 (s, 3H), 3.24 (m, 2H), 1.92 (t, 2H), 1.38-1.18 (m, 4H), 1.04-
0.93 (m, 2H). 7 ##STR00093## LC-MS (method 1): R.sub.t = 2.86 min;
m/z = 448 (M + H).sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.
= 8.28 (s, 1H), 7.20-7.02 (m, 9H), 4.63 (m, 1H), 3.11 (m, 2H), 2.59
(m, 2H), 2.00 (m, 2H), 1.36 (m, 2H), 1.22-0.95 (m, 7H).
General Procedure C
Cleavage of Tert-Butyl Esters to the Corresponding Carboxylic
Acids
[0561] At from 0.degree. C. to RT, TFA is added dropwise to a
solution of the tert-butyl ester in dichloromethane (concentration
from 0.05 to 1.0 mol/l; additionally one drop of water), until a
dichloromethane/TFA ratio of about 2:1 to 1:1 is reached. The
mixture is stirred at RT for 1-18 h and then concentrated under
reduced pressure. The residue is purified by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient).
The Working Examples Below are Obtained According to General
Procedure C:
TABLE-US-00003 [0562] Example Structure Analytical data 8
##STR00094## LC-MS (method 3): R.sub.t = 4.05 min; m/z = 463 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 11.95 (s,
1H), 8.64 (s, 1H), 7.86- 7.75 (m, 5H), 7.19 (d, 2H), 6.90 (d, 2H),
5.20 (m, 1H), 3.78 (s, 3H), 2.08 (t, 2H), 1.43-1.18 (m, 4H), 1.12
(d, 3H), 1.07-0.88 (m, 2H). [.alpha.].sub.D.sup.20 = -54.degree., c
= 0.455, chloroform. 9 ##STR00095## LC-MS (method 3): R.sub.t =
4.40 min; m/z = 461 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. = 11.95 (br. s, 1H), 8.65 (s, 1H), 7.85-
7.75 (m, 5H), 7.18 (m, 4H), 5.18 (m, 1H), 2.65 (q, 2H), 2.07 (t,
2H), 1.40-1.12 (m, 4H), 1.20 (t, 3H), 1.09 (d, 3H), 1.03-0.89 (m,
2H). [.alpha.].sub.D.sup.20 = -51.degree., c = 0.575,
chloroform.
Example 10
Ethyl
6-{[3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}hexanoate
##STR00096##
[0564] Under an atmosphere of argon, 100 mg (0.32 mmol) of
3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-ol are dissolved in 0.6
ml of DMF, and 103 mg (0.32 mmol) of cesium carbonate, 10 mg (0.06
mmol) of potassium iodide and 88 mg (0.40 mmol) of ethyl
6-bromohexanoate are added. After 1 h of stirring at RT, another 51
mg (0.16 mmol) of cesium carbonate and 35 mg (0.16 mmol) of ethyl
6-bromohexanoate are added and the mixture is stirred at RT
overnight. Water is added, the reaction mixture is saturated with
sodium chloride and extracted with ethyl acetate, the combined
extracts are dried over magnesium sulfate and the organic phase is
concentrated under reduced pressure. The residue is purified by
preparative RP-HPLC using a mobile phase of water and acetonitrile.
118 mg (81% of theory) of the target compound are isolated.
[0565] LC-MS (method 1): R.sub.t=3.51 min; m/z=459 (M+H).sup.+
[0566] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.49 (d, 2H),
7.38-7.21 (m, 7H), 6.99 (d, 2H), 6.71 (d, 1H), 4.05 (q, 2H), 3.85
(t, 2H), 3.70 (s, 3H), 2.15 (t, 2H), 1.48-1.31 (m, 4H), 1.18 (t,
3H), 0.94 (m, 2H).
Example 11
tert-Butyl
(6R)-6-{[3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}hep-
tanoate
##STR00097##
[0568] Under argon, 130 mg (0.41 mmol) of
3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-ol of are initially
charged in 0.5 ml of DMF, and 136.2 mg (0.51 mmol) of tert-butyl
(+)-(6S)-6-bromoheptanoate, 133.9 mg (0.41 mmol) of cesium
carbonate and 13 mg (0.08 mmol) of potassium iodide are added in
succession. The mixture is stirred at RT overnight and then diluted
with water. The mixture is saturated with sodium chloride and
extracted three times with ethyl acetate. The combined organic
phases are dried over magnesium sulfate and concentrated under
reduced pressure. The crude product is purified by preparative
RP-HPLC. 161 mg (78.3% of theory) of the target compound are
isolated.
[0569] LC-MS (method 1): R.sub.t=3.68 min; m/z=523 (M+Na).sup.+
[0570] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.49 (d, 2H),
7.38-7.19 (m, 7H), 6.99 (d, 2H), 6.75 (d, 1H), 4.37 (m, 1H), 3.81
(s, 3H), 2.07 (t, 2H), 1.39 (s, 9H), 1.38-1.25 (m, 4H), 1.07 (d,
3H), 1.05-0.95 (m, 2H).
[0571] [.alpha.].sub.D.sup.20=-63.5.degree., c=0.535,
chloroform.
Example 12
6-{[3-(4-Methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}hexanoic
acid
##STR00098##
[0573] Under an atmosphere of argon, 90 mg (0.20 mmol) of ethyl
6-{[3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}hexanoate
are suspended in 1 ml of ethanol, and 0.8 ml of 2.5 M aqueous
sodium hydroxide solution is added. After 1 h of stirring at RT,
another 0.8 ml of 2.5 M aqueous sodium hydroxide solution is added
and the mixture is stirred at 40.degree. C. for 1 h. For work-up,
the cooled reaction solution is made slightly acidic using 1 M
hydrochloric acid, and the resulting precipitate is filtered off.
The precipitate is washed repeatedly with water and then triturated
with a little methanol, filtered off and dried under reduced
pressure. This gives 47 mg (56% of theory) of the title
compound.
[0574] LC-MS (method 4): R.sub.t=2.79 min; m/z=431 (M+H).sup.+
[0575] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=11.98 (br. s,
1H), 7.48 (d, 2H), 7.38-7.20 (m, 7H), 6.99 (d, 2H), 6.71 (d, 1H),
3.87 (t, 2H), 3.71 (s, 3H), 2.09 (t, 2H), 1.48-1.28 (m, 4H), 0.94
(m, 2H).
Example 13
(6R)-6-{[3-(4-Methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}heptanoic
acid
##STR00099##
[0577] 60 mg (0.12 mmol) of tert-butyl
(6R)-6-{[3-(4-methoxyphenyl)-2-phenyl-1-benzofuran-4-yl]oxy}heptanoate
are dissolved in 0.5 ml of dichloromethane. After addition of a
drop of water, about 0.1 ml of trifluoroacetic acid is added and
the mixture is stirred at RT for 30 min. Another 0.1 ml of TFA is
added, and the mixture is then stirred for another 30 min. The
reaction mixture is concentrated under reduced pressure and the
residue is dried under high vacuum. The crude product is initially
pre-purified by preparative RP-HPLC, and the product obtained is
purified further by trituration with methanol and filtration. 7 mg
(13.1% of theory) of the target compound are isolated.
[0578] LC-MS (method 10): R.sub.t=3.68 min; m/z (ESIneg)=443
(M-H).sup.-
[0579] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=11.96 (br. s,
1H), 7.50 (d, 2H), 7.38-7.18 (m, 7H), 6.99 (d, 2H), 6.73 (d, 1H),
4.36 (m, 1H), 3.82 (s, 3H), 2.09 (t, 2H), 1.38-1.22 (m, 4H), 1.05
(d, 3H), 1.05-0.95 (m, 2H).
Example 14
tert-Butyl
(6R)-6-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]ox-
y}heptanoate
##STR00100##
[0581] Under an atmosphere of argon, 100 mg (0.30 mmol) of
4-chloro-3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridine and 73 mg
(0.36 mmol) of tert-butyl (-)-6-hydroxyheptanoate are dissolved in
1 ml of DMF. At 0.degree. C., 0.4 ml (0.36 mmol) of a 1 M solution
of
N'''-tert-butyl-N,N',N'''-tris[tris(dimethylamino)phosphoranylidene]-phos-
phorimidetriamide in hexane is then added. The reaction mixture is
stirred at 0.degree. C. for 1 h and then slowly warmed to RT and
stirred at RT for a further 2 h. Water is added, and the mixture is
saturated with sodium chloride and extracted three times with ethyl
acetate. The combined extracts are dried over sodium sulfate and
concentrated on a rotary evaporator. The crude product is purified
by preparative RP-HPLC using a gradient of water and acetonitrile.
This gives 21 mg of the target product (12.9% of theory).
[0582] LC-MS (method 4): R.sub.t=3.44 min; m/z=502 (M+H).sup.+
[0583] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.01 (d, 1H),
7.51 (d, 2H), 7.41-7.29 (m, 6H), 6.99 (d, 2H), 5.13 (m, 1H), 3.82
(s, 3H), 2.08 (t, 2H), 1.49-1.29 (m, 4H), 1.35 (s, 9H), 1.21-0.97
(m, 2H), 1.17 (d, 3H).
Example 15
tert-Butyl
6-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}h-
exanoate
##STR00101##
[0585] Under an atmosphere of argon, 100 mg (0.30 mmol) of
4-chloro-3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridine are
initially charged in 1 ml of toluene, and 34 mg (0.36 mmol) of
sodium tert-butoxide, 7 mg (0.01 mmol) of
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 55 mg (0.06 mmol)
of tris(dibenzylideneacetone)dipalladium and 89 mg (0.48 mmol) of
tert-butyl 6-amino-hexanoate are successively added. The mixture is
stirred under reflux for 1 h. The cooled reaction mixture is then
diluted with dichloromethane, water is added, the catalyst and the
salts are filtered off through Celite and the filter residue is
washed with dichloromethane and concentrated under reduced
pressure. The crude product is purified by preparative RP-HPLC
(gradient of acetonitrile and water). This gives 96 mg (66% of
theory) of the title compound.
[0586] LC-MS (method 5): R.sub.t=1.82 min; m/z=487 (M+H).sup.+
[0587] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.93 (d, 1H),
7.45 (d, 4H), 7.39-7.26 (m, 3H), 7.15 (m, 2H), 6.95 (d, 1H), 4.31
(t, 1H), 3.86 (s, 3H), 3.25 (q, 2H), 2.13 (t, 2H), 1.45-1.25 (m,
4H), 1.38 (s, 9H), 1.11-0.99 (m, 2H).
Example 16
tert-Butyl
(3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-
-2,2-dimethylpropoxy)acetate
##STR00102##
[0589] 123 mg (1.54 mmol) of 50% strength aqueous sodium hydroxide
solution and 0.2 ml of toluene are warmed to 40.degree. C., and 5
mg (0.02 mmol) of tetra-N-butylammonium hydrogensulfate are added.
A solution of 62 mg (0.15 mmol) of
3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-2,2-dimeth-
ylpropan-1-ol in 0.2 ml of toluene and 46 .mu.l (0.31 mmol) of
tert-butyl bromoacetate are then added dropwise. The mixture is
then stirred at 60.degree. C. for 4 h. After cooling, the mixture
is diluted with water and then extracted three times with ethyl
acetate. The combined extracts are dried over magnesium sulfate and
concentrated under reduced pressure. The crude product is purified
by preparative RP-HPLC (gradient of water and acetonitrile). This
gives 35 mg (56% of theory) of the title compound.
[0590] LC-MS (method 1): R.sub.t=2.25 min; m/z=517 (M+H).sup.+
[0591] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.90 (d, 1H),
7.50-7.40 (m, 4H), 7.37-7.26 (m, 3H), 7.15 (d, 2H), 6.94 (d, 1H),
4.49 (t, 1H), 3.85 (s, 3H), 3.75 (s, 2H), 3.25 (d, 2H), 2.98 (s,
2H), 1.40 (s, 9H), 0.69 (s, 6H).
Example 17
(6R)-6-{[3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]oxy}heptanoic
acid
##STR00103##
[0593] 13 mg (0.03 mmol) of tert-butyl
(6R)-6-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]oxy}heptanoa-
te are dissolved in 1 ml of dichloromethane, 40 .mu.l (59 mg, 0.52
mmol) of trifluoroacetic acid are added and the mixture is stirred
at RT for 3 h. The reaction mixture is then diluted with
dichloromethane and washed with water and sat. sodium chloride
solution, the organic phase is dried over sodium sulfate and
concentrated on a rotary evaporator and the residue is dried under
reduced pressure. This gives 11 mg (93% of theory) of the target
compound.
[0594] LC-MS (method 5): R.sub.t=2.52 min; m/z=446 (M+H).sup.+
[0595] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=11.95 (s, 1H),
8.01 (d, 1H), 7.52 (d, 2H), 7.41-7.29 (m, 6H), 7.01 (d, 2H), 5.14
(m, 1H), 3.82 (s, 3H), 2.10 (t, 2H), 1.50-1.30 (m, 4H), 1.21-0.97
(m, 2H), 1.17 (d, 3H).
[0596] [.alpha.].sub.D.sup.20=-64.degree., c=0.420, chloroform.
Example 18
6-{[3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}hexanoic
acid
##STR00104##
[0598] 69 mg (0.14 mmol) of tert-butyl
6-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}hexanoate
are dissolved in 2 ml of dichloromethane, 0.2 ml of trifluoroacetic
acid is added and the mixture is stirred at RT for 3 h. The
reaction mixture is diluted with dichloromethane and washed with
water and sat. sodium chloride solution, the organic phase is dried
over sodium sulfate and concentrated under reduced pressure and the
residue is chromatographed on silica gel (mobile phase:
dichloromethane/methanol 10:1). This gives 48 mg (79% of theory) of
the target compound.
[0599] LC-MS (method 1): R.sub.t=1.81 min; m/z=431 (M+H).sup.+
[0600] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=12.01 (br. s,
1H), 7.92 (d, 1H), 7.45 (d, 4H), 7.39-7.27 (m, 3H), 7.15 (m, 2H),
6.95 (d, 1H), 4.31 (t, 1H), 3.86 (s, 3H), 3.25 (q, 2H), 2.15 (t,
2H), 1.41 (m, 2H), 1.32 (m, 2H), 1.06 (m, 2H).
Example 19
(3-{[3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-2,2-dimeth-
ylpropoxy)acetic acid
##STR00105##
[0602] 25 mg (0.05 mmol) of tert-butyl
(3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}-2,2-dimet-
hylpropoxy)acetate are stirred with 37 .mu.l of trifluoroacetic
acid and a drop of water at RT for 10 min. The trifluoroacetic acid
and the water are then removed on a rotary evaporator, ethyl
acetate is added to the residue and the mixture is washed once with
sat. sodium bicarbonate solution. The aqueous phase is re-extracted
twice with ethyl acetate. The combined organic phases are dried
over magnesium sulfate and concentrated under reduced pressure.
Drying of the residue under high vacuum gives 7 mg (32% of theory)
of the title compound.
[0603] LC-MS (method 1): R.sub.t=1.93 min; m/z=461 (M+H).sup.+
[0604] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=12.54 (br. s,
1H), 7.90 (d, 1H), 7.50-7.40 (m, 4H), 7.36-7.26 (m, 3H), 7.16 (d,
2H), 6.94 (d, 1H), 4.47 (t, 1H), 3.85 (s, 3H), 3.79 (s, 2H), 3.25
(d, 2H), 2.99 (s, 2H), 0.69 (s, 6H).
Example 20
tert-Butyl
3-(3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-
-2,2-dimethylpropoxy)propanoate
##STR00106##
[0606] 150 mg (0.375 mmol) of
3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-2,2-dimethyl-
propan-1-ol are, together with 240 mg (1.873 mmol) of tert-butyl
acrylate and 25 mg (0.075 mmol) of tetra-N-butylammonium
hydrogensulfate, initially charged in 3.75 ml of dichloromethane
and cooled to 0.degree. C. 0.75 ml of 50% strength aqueous sodium
hydroxide solution is added, and the mixture is stirred vigorously
at 0.degree. C. for 20 min. The mixture is then allowed to warm to
room temperature and stirred vigorously for another 3 h. The
mixture is diluted with a little dichloromethane and water and
acidified with 10% strength citric acid, and the phases are
separated. The aqueous phase is re-extracted with dichloromethane.
The combined organic phases are washed once with sat. sodium
chloride solution, dried over magnesium sulfate and concentrated.
The residue is purified on silica gel by preparative thick-layer
chromatography (mobile phase: cyclohexane/ethyl acetate 7:3). The
pure zone is scraped off and extracted with
dichloromethane/methanol (95:5). The solvent is removed and the
residue is dried under high vacuum, which gives 150 mg (75.8% of
theory) of the target compound.
[0607] LC-MS (method 2): R.sub.t=4.97 min; m/z=529 (M+H).sup.+
[0608] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.98 (d, 1H),
7.56-7.51 (m, 2H), 7.42 (d, 2H), 7.34 (d, 2H), 7.26-7.19 (m, 3H),
6.29 (d, 1H), 4.26-4.22 (t, 1H), 3.52-3.48 (t, 2H), 2.92-2.87 (m,
4H), 2.78-2.71 (q, 2H), 2.41-2.36 (t, 2H), 1.41 (s, 9H), 1.31-1.26
(t, 3H), 0.64 (s, 6H).
Example 21
3-(3-{[3-(4-Ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-2,2-dimeth-
ylpropoxy)-propanoic acid
##STR00107##
[0610] 150 mg (0.284 mmol) of tert-butyl
3-(3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}-2,2-dimet-
hylpropoxy)propanoate are dissolved in 3 ml of dichloromethane.
0.75 ml of trifluoroacetic acid is added, and the mixture is
stirred at room temperature for 2 h. The mixture is then evaporated
to dryness, and the residue is purified on silica gel by
preparative thick-layer chromatography (mobile phase
dichloromethane/methanol 95:5). The pure zone is scraped off and
extracted with dichloromethane/methanol (9:1). The solvent is
removed and the residue is dried under high vacuum, which gives 85
mg (63.4% of theory) of the target compound.
[0611] LC-MS (method 1): R.sub.t=2.87 min; m/z=473 (M+H).sup.+
[0612] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.86 (d, 1H),
7.47-7.40 (m, 4H), 7.34 (d, 2H), 7.15 (m, 3H), 6.22 (d, 1H),
4.36-4.32 (t, 1H), 3.65-3.62 (t, 2H), 2.96-2.92 (m, 4H), 2.79-2.70
(q, 2H), 2.57-2.54 (t, 2H), 1.32-1.27 (t, 3H), 0.64 (s, 6H).
Example 22
tert-Butyl
6-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]amino}hex-
anoate
##STR00108##
[0614] 50 mg (0.15 mmol) of
4-chloro-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine are
initially charged in 1 ml of toluene, and 17 mg (0.18 mmol) of
sodium tert-butoxide, 4 mg (0.01 mmol) of
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 27 mg (0.03 mmol)
of tris(dibenzylideneacetone)dipalladium and 45 mg (0.24 mmol) of
tert-butyl 6-aminohexanoate are added in succession. The reaction
mixture is stirred under reflux overnight. The cooled mixture is
then diluted with dichloromethane, water is added, the catalyst is
filtered off through Celite, the filtrate is washed with water and
sat. sodium chloride solution and the organic phase is dried over
sodium sulfate and concentrated under reduced pressure. The crude
product is chromatographed on silica gel using a mobile phase of
cyclohexane and ethyl acetate (2:1). This gives 44 mg (57% of
theory) of the title compound.
[0615] LC-MS (method 1): R.sub.t=3.52 min; m/z=485 (M+H).sup.+
[0616] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.95 (d, 1H),
7.49-7.40 (m, 5H), 7.37-7.23 (m, 4H), 6.41 (d, 1H), 4.15 (t, 2H),
3.02 (q, 1H), 2.75 (q, 2H), 2.11 (t, 2H), 1.45-1.21 (m, 16H),
1.09-0.99 (m, 2H).
Example 23
tert-Butyl
(3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}prop-
oxy)acetate
##STR00109##
[0618] 70 mg (0.19 mmol) of
3-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}propan-1-ol
and 30 .mu.l (0.20 mmol) of tert-butyl bromoacetate are initially
charged in 2 ml of DMF, 0.2 ml (126 mg, 0.20 mmol) of a 1 M
solution of
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosph-
orimidetriamide in hexane is added at 0.degree. C. and the mixture
is stirred initially at 0.degree. C. for 4 h and then at RT
overnight. At 0.degree. C., another 30 .mu.l (0.20 mmol) of
tert-butyl bromoacetate and 0.2 ml (126 mg, 0.20 mmol) of 1 M
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosph-
orimidetriamide solution in hexane are then added, and the mixture
is stirred at RT for a further 12 h. Water is added, and the
reaction mixture is neutralized with 1 M hydrochloric acid and
extracted with dichloromethane. The extract is washed with sat.
sodium chloride solution, dried over sodium sulfate and
concentrated on a rotary evaporator. The crude product is
pre-purified by chromatography on silica gel (gradient
dichloromethane/methanol 100:1.fwdarw.50:1). Final fine
purification by preparative RP-HPLC (gradient of water and
acetonitrile) gives 19 mg (20% of theory) of the title
compound.
[0619] LC-MS (method 5): R.sub.t=2.88 min; m/z=488 (M+H).sup.+
[0620] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.18 (d, 1H),
7.52 (dd, 2H), 7.39-7.29 (m, 5H), 7.27 (d, 2H), 6.93 (d, 1H), 4.55
(m, 1H), 3.79 (s, 2H), 3.12 (t, 2H), 2.69 (q, 2H), 1.70 (m, 2H),
1.39 (s, 9H), 1.23 (t, 3H).
Example 24
tert-Butyl
(6R)-6-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}-
heptanoate
##STR00110##
[0622] 80 mg (0.24 mmol) of
4-chloro-3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridine and 107 mg
(0.53 mmol) of tert-butyl (-)-6-hydroxyheptanoate are dissolved in
1 ml of DMF. At 0.degree. C., 0.5 ml (304 mg, 0.48 mmol) of a 1 M
solution of
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosph-
orimidetriamide in hexane are then added and the reaction mixture
is stirred at -5.degree. C. to 0.degree. C. for 2.5 h. Water is
then added, and the mixture is neutralized with 1 M hydrochloric
acid and extracted with dichloromethane. The organic phase is
washed with sat. sodium chloride solution, dried over sodium
sulfate and concentrated on a rotary evaporator. The crude product
is chromatographed on silica gel (mobile phase: cyclohexane/ethyl
acetate 3:1). This gives 27 mg (18% of theory) of the title
compound.
[0623] LC-MS (method 5): R.sub.t=3.19 min; m/z=500 (M+H).sup.+
[0624] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.18 (d, 1H),
7.52 (dd, 2H), 7.41-7.30 (m, 5H), 7.28 (d, 2H), 6.93 (d, 1H), 4.57
(m, 1H), 2.74-2.64 (m, 2H), 2.07 (t, 2H), 1.45-1.20 (m, 3H), 1.34
(s, 9H), 1.23 (t, 3H), 1.13 (d, 3H), 1.03 (m, 2H).
Example 25
tert-Butyl
3-(2-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}et-
hoxy)propanoate
##STR00111##
[0626] 65 mg (0.18 mmol) of
2-{[3-(4-ethylphenyl)-2-phenylfuro[2,3-b]pyridin-4-yl]oxy}ethanol
and 24 mg (0.19 mmol) of tert-butyl acrylate are dissolved in 2 ml
of DMF, 0.2 ml (126 mg, 0.20 mmol) of a 1 M solution of
N'''-tert-butyl-N,N',N''-tris-[tris(dimethylamino)phosphoranylidene]phosp-
horimidetriamide in hexane is added at 0.degree. C. and the mixture
is stirred at 0.degree. C. for 2.5 h. Water is then added to the
reaction mixture, and the mixture is neutralized with 1 M
hydrochloric acid and extracted with dichloromethane. The organic
phase is washed with sat. sodium chloride solution, dried over
sodium sulfate and concentrated on a rotary evaporator. The residue
is dissolved in 2 ml of DMF, another 48 mg (0.38 mmol) of
tert-butyl acrylate and 0.4 ml (252 mg, 0.40 mmol) of 1 M
N'''-tert-butyl-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosph-
orimidetriamide solution in hexane are added at 0.degree. C. and
the mixture is stirred at RT overnight. The reactions are worked up
as described above and the residue obtained is reacted at 0.degree.
C. with a further 232 mg (1.81 mmol) of tert-butyl acrylate and 8
mg (0.20 mmol) of 60% sodium hydride. The reaction mixture is then
stirred at RT for a further night. After the extractive work-up
described above, the dried residue is finally purified by
preparative RP-HPLC (gradient of water and acetonitrile). In this
manner, 22 mg (25% of theory) of the title compound are
obtained.
[0627] LC-MS (method 4): R.sub.t=3.05 min; m/z=488 (M+H).sup.+
[0628] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.21 (d, 1H),
7.51 (dd, 2H), 7.41-7.30 (m, 5H), 7.27 (d, 2H), 6.95 (d, 1H), 4.15
(t, 2H), 3.51 (t, 2H), 3.38 (t, 2H), 2.68 (q, 2H), 2.31 (t, 2H),
1.35 (s, 9H), 1.24 (t, 3H).
The Working Examples Below are Obtained According to General
Procedure C:
TABLE-US-00004 [0629] Example Structure Analytical data 26
##STR00112## LC-MS (method 4): R.sub.t = 2.30 min; m/z = 429 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 12.01 (br.
s, 1H), 7.95 (d, 1H), 7.49- 7.39 (m, 6H), 7.38-7.25 (m, 3H), 6.41
(d, 1H), 4.15 (t, 1H), 3.02 (q, 2H), 2.73 (q, 2H), 2.14 (t, 2H),
1.39 (m, 2H), 1.33-1.22 (m, 5H), 1.05 (m, 2H). 27 ##STR00113##
LC-MS (method 1): R.sub.t = 2.83 min; m/z = 432 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. = 8.21 (d, 1H), 7.51
(dd, 2H), 7.41- 7.30 (m, 5H), 7.28 (d, 2H), 6.94 (d, 1H), 4.08 (t,
2H), 3.63 (m, 2H), 3.17 (t, 2H), 2.73-2.64 (m, 2H), 1.69 (m, 2H),
1.24 (t, 3H). 28 ##STR00114## LC-MS (method 4): R.sub.t = 2.67 min;
m/z = 444 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. = 11.95 (br. s, 1H), 8.17 (d, 1H), 7.52 (dd, 2H), 7.40-7.31
(m, 5H), 7.27 (d, 2H), 6.93 (d, 1H), 4.55 (m, 1H), 2.69 (q, 2H),
2.09 (t, 2H), 1.45-1.19 (m, 4H), 1.25 (t, 3H), 1.12 (d, 3H), 1.05
(m, 2H). [.alpha.].sub.D.sup.20 = -94.degree., c = 0.090,
chloroform. 29 ##STR00115## LC-MS (method 1): R.sub.t = 2.78 min;
m/z = 432 (M + H).sup.+. .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta.
= 8.16 (d, 1H), 7.55 (m, 2H), 7.39 (d, 2H), 7.33- 7.24 (m, 5H),
6.91 (d, 1H), 4.20 (m, 2H), 3.59 (m, 2H), 3.45 (t, 2H), 2.74 (m,
2H), 2.40 (t, 2H), 1.37-1.25 (m, 3H).
Example 30
Methyl
(3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}phen-
oxy)acetate
##STR00116##
[0631] 200 mg (0.596 mmol) of
4-chloro-3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridine, 129.5 mg
(0.715 mmol) of methyl 3-aminophenoxyacetate and 135 .mu.l (0.893
mmol) of triethylamine are mixed and heated to about 200.degree. C.
using a hot-air blower. Using the hot-air blower, the melt formed
is heated even more and then briefly (for a few minutes) heated to
the boil. After cooling, the target product is isolated directly by
chromatography of the reaction mixture on silica gel (Biotage,
gradient: cyclohexane/ethyl acetate 10:1.fwdarw.5:1). In this
manner, 75 mg (26.2% of theory) of the title compound are
obtained.
[0632] LC-MS (method 1): R.sub.t=2.90 min; m/z=481 (M+H).sup.+
[0633] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.12 (d, 1H),
7.59 (d, 2H), 7.53 (d, 2H), 7.42-7.34 (m, 3H), 7.29-7.24 (m, 4H),
7.14 (t, 1H), 6.64 (d, 1H), 6.55 (s, 1H), 5.98 (d, 1H), 4.72 (s,
2H), 3.92 (s, 3H), 3.71 (s, 3H).
Example 31
(3-{[3-(4-Methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}phenoxy)ace-
tic acid
##STR00117##
[0635] 54.0 mg (0.112 mmol) of methyl
(3-{[3-(4-methoxyphenyl)-2-phenylfuro[3,2-c]pyridin-4-yl]amino}phenoxy)ac-
etate are initially charged in 0.5 ml of methanol, and 1.1 ml of 1
N aqueous sodium hydroxide solution are added at RT. After 30 min
of stirring, 1 N hydrochloric acid is added and the reaction
mixture is extracted three times with ethyl acetate. The combined
organic phases are dried over magnesium sulfate and concentrated
under reduced pressure. The residue is purified by preparative
RP-HPLC (water/acetonitrile gradient). The product obtained in this
manner is purified further by chromatography on silica gel
(gradient: dichloromethane.fwdarw.dichloromethane/methanol 10:1).
This gives 32 mg of the title compound (61% of theory).
[0636] LC-MS (method 10): R.sub.t=1.25 min; m/z=467 (M+H).sup.+
[0637] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.15 (d, 1H),
7.60 (d, 2H), 7.52 (d, 2H), 7.42-7.33 (m, 3H), 7.30-7.25 (m, 4H),
7.11 (t, 1H), 6.61 (dd, 1H), 6.53 (s, 1H), 6.45 (dd, 1H), 4.54 (s,
2H), 3.93 (s, 3H).
B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY
[0638] The pharmacological action of the compounds according to the
invention can be demonstrated in the following assays:
B-1. Studies of Binding to Prostacyclin Receptors (IP Receptors) of
Human Thrombocyte Membranes
[0639] Thrombocyte membranes are obtained by centrifuging 50 ml of
human blood (Buffy coats with CDP Stabilizer, from Maco Pharma,
Langen) for 20 min at 160.times.g. Remove the supernatant
(platelet-rich plasma, PRP) and then centrifuge again at
2000.times.g for 10 min at room temperature. Resuspend the sediment
in 50 mM tris(hydroxymethyl)aminomethane, which has been adjusted
to a pH of 7.4 with 1 N hydrochloric acid, and store at -20.degree.
C. overnight. On the next day, centrifuge the suspension at 80
000.times.g and 4.degree. C. for 30 min. Discard the supernatant.
Resuspend the sediment in 50 mM
tris(hydroxymethyl)aminomethane/hydrochloric acid, 0.25 mM ethylene
diamine tetraacetic acid (EDTA), pH 7.4, and then centrifuge once
again at 80 000.times.g and 4.degree. C. for 30 min. Take up the
membrane sediment in binding buffer (50 mM
tris(hydroxymethyl)-aminomethane/hydrochloric acid, 5 mM magnesium
chloride, pH 7.4) and store at -70.degree. C. until the binding
test.
[0640] For the binding test, incubate 3 nM .sup.3H-Iloprost (592
GBq/mmol, from AmershamBioscience) for 60 min with 300-1000
.mu.g/ml of human thrombocyte membranes per charge (max. 0.2 ml) in
the presence of the test substances at room temperature. After
stopping, add cold binding buffer to the membranes and wash with
0.1% bovine serum albumin. After adding Ultima Gold Scintillator,
quantify the radioactivity bound to the membranes using a
scintillation counter. The nonspecific binding is defined as
radioactivity in the presence of 1 .mu.M Iloprost (from Cayman
Chemical, Ann Arbor) and is as a rule <25% of the bound total
radioactivity. The binding data (IC.sub.50 values) are determined
using the program GraphPad Prism Version 3.02.
Representative Results for the Compounds According to the Invention
are Shown in Table 1:
TABLE-US-00005 [0641] TABLE 1 Example No. IC.sub.50 [nM] 5 39 9 208
12 984 19 98 21 35 28 39 29 1703
B-2. IP-Receptor Stimulation on Whole Cells
[0642] The IP-agonistic action of test substances is determined by
means of the human erythroleukaemia cell line (HEL), which
expresses the IP-receptor endogenously [Murray, R., FEBS Letters
1989, 1: 172-174]. For this, the suspension cells (4.times.10.sup.7
cells/ml) are incubated with the particular test substance for 5
minutes at 30.degree. C. in buffer [10 mM HEPES
(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)/PBS
(phosphate-buffered saline, from Oxoid, UK)], 1 mM calcium
chloride, 1 mM magnesium chloride, 1 mM IBMX
(3-isobutyl-1-methylxanthine), pH 7.4. Next, the reaction is
stopped by addition of 4.degree. C. cold ethanol and the charges
are stored for a further 30 minutes at 4.degree. C. Then the
samples are centrifuged at 10 000.times.g and 4.degree. C. The
resultant supernatant is discarded and the sediment is used for
determination of the concentration of cyclic adenosine
monophosphate (cAMP) in a commercially available
cAMP-radioimmunoassay (from IBL, Hamburg). In this test, IP
agonists lead to an increase in cAMP concentration, but IP
antagonists have no effect. The effective concentration (EC.sub.50
value) is determined using the program GraphPad Prism Version
3.02.
B-3. Inhibition of Thrombocyte Aggregation In Vitro
[0643] Inhibition of thrombocyte aggregation is determined using
blood from healthy test subjects of both sexes. Mix 9 parts blood
with one part 3.8% sodium citrate solution as coagulant. Centrifuge
the blood at 900 rev/min for 20 min. Adjust the pH value of the
platelet-rich plasma obtained to pH 6.5 with ACD solution (sodium
citrate/citric acid/glucose). Then remove the thrombocytes by
centrifugation, take up in buffer and centrifuge again. Take up the
thrombocyte deposit in buffer and additionally resuspend with 2
mmol/l calcium chloride.
[0644] For the measurements of aggregation, incubate aliquots of
the thrombocyte suspension with the test substance for 10 min at
37.degree. C. Next, aggregation is induced by adding ADP and is
determined by the turbidometric method according to Born in the
aggregometer at 37.degree. C. [Born G. V. R., J. Physiol. (London)
168, 178-179 (1963)].
B-4. Measurement of Blood Pressure of Anaesthetized Rats
[0645] Anaesthetize male Wistar rats with a body weight of 300-350
g with thiopental (100 mg/kg i.p.). After tracheotomy, catheterize
the arteria femoralis for blood pressure measurement. Administer
the test substances as solution, orally by oesophageal tube or
intravenously via the femoral vein in a suitable vehicle.
B-5. PAH Model in the Anaesthetized Dog
[0646] In this animal model of pulmonary arterial hypertension
(PAH), mongrel dogs having a body weight of about 25 kg are used.
Narcosis is induced by slow i.v. administration of 25 mg/kg of
sodium thiopental (Trapanal.RTM.) and 0.15 mg/kg of alcuronium
chloride (Alloferin.RTM.) and maintained during the experiment by
continuous infusion of 0.04 mg/kg/h of Fentanyl.RTM., 0.25 mg/kg/h
of droperidol (Dehydro-benzperidol.RTM.) and 15 .mu.g/kg/h of
alcuronium chloride (Alloferin.RTM.). Reflectory effects on the
pulse by lowering of the blood pressure are kept to a minimum by
autonomous blockage [continuous infusion of atropin (about 10
.mu.g/kg/h) and propranolol (about 20 .mu.g/kg/h)]. After
intubation, the animals are ventilated using a ventilator with
constant tidal volume such that an end-tidal CO.sub.2 concentration
of about 5% is reached. Ventilation takes place with ambient air
enriched with about 30% oxygen (normoxa). For measuring the
hemodynamic parameters, a liquid-filled catheter is implanted into
the femoralis artery for measuring the blood pressure. A
double-lumiger Swan-Ganz.RTM. catheter is introduced via the
jugulara vein into the pulmonary artery (distal lumen for measuring
the pulmonary arterial pressure, proximal lumen for measuring the
central venus pressure). The left-ventricular pressure is measured
following introduction of a micro-tip catheter (Millar.RTM.
Instruments) via the carotis artery into the left ventricle, and
from this, the dP/dt value is derived as a measure for the
contractility. Substances are administered i.v. via the femoralis
vein. The hemodynamic signals are recorded and evaluated using
pressure sensors/amplifiers and PONEMAH.RTM. as data acquisition
software.
[0647] To induce acute pulmonary hypertension, the stimulus used is
either hypoxia or continuous infusion of thromboxan A.sub.2 or a
thromboxan A.sub.2 analog. Acute hypoxia is induced by gradually
reducing the oxygen in the ventilation air to about 14%, such that
the mPAP increases to values of >25 mm Hg. If the stimulus used
is a thromboxan A.sub.2 analog, 0.21-0.32 .mu.g/kg/min of U-46619
[9,11-dideoxy-9.alpha.,11.alpha.-epoxymethanoprostaglandin
F.sub.2.alpha. (from Sigma)] are infused to increase the mPAP to
>25 mm Hg.
B-6. PAH Model in Anaesthetized Gottingen Minipiq
[0648] In this animal model of pulmonary arterial hypertension
(PAH), Gottingen Minipigs having a body weight of about 25 kg are
used. Narcosis is induced by 30 mg/kg of ketamine (Ketavet.RTM.)
i.m., followed by i.v. administration of 10 mg/kg of sodium
thiopental (Trapanal.RTM.); during the experiment, it is maintained
by inhalation narcosis using enfluran (2-2.5%) in a mixture of
ambient air enriched with about 30-35% oxygen/N.sub.2O (1:1.5). For
measuring the hemodynamic parameters, a liquid-filled catheter is
implanted into the coratid artery for measuring the blood pressure.
A double-lumiger Swan-Ganz.RTM. catheter is introduced via the
jugulara vein into the pulmonary artery (distal lumen for measuring
the pulmonary arterial pressure, proximal lumen for measuring the
central venus pressure). The left-ventricular pressure is measured
following introduction of a micro-tip catheter (Millar.RTM.
Instruments) via the carotis artery into the left ventricle, and
from this, the dP/dt value is derived as a measure for the
contractility. Substances are administered i.v. via the femoralis
vein. The hemodynamic signals are recorded and evaluated using
pressure sensors/amplifiers and PONEMAH.RTM. as data acquisition
software.
[0649] To induce acute pulmonary hypertension, the stimulus used is
continuous infusion of a thromboxan A.sub.2 analog. Here, 0.12-0.14
.mu.g/kg/min of U-46619
[9,11-dideoxy-9.alpha.,11.alpha.-epoxymethanoprostaglandin
F.sub.2.alpha. (from Sigma)] are infused to increase the mPAP to
>25 mm Hg.
C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS
[0650] The compounds of the invention can be converted into
pharmaceutical preparations in the following ways:
Tablet:
Composition:
[0651] 100 mg of the compound of the invention, 50 mg of lactose
(monohydrate), 50 mg of corn starch (native), 10 mg of
polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany)
and 2 mg of magnesium stearate.
[0652] Tablet weight 212 mg, diameter 8 mm, radius of curvature 12
mm.
Production:
[0653] The mixture of compound of the invention, lactose and starch
is granulated with a 5% strength solution (m/m) of the PVP in
water. The granules are mixed with the magnesium stearate for 5
minutes after drying. This mixture is compressed with a
conventional tablet press (see above for format of the tablet). A
guideline compressive force for the compression is 15 kN.
Suspension which can be Administered Orally:
Composition:
[0654] 1000 mg of the compound of the invention, 1000 mg of ethanol
(96%), 400 mg of Rhodigel.RTM. (xanthan gum from FMC, Pennsylvania,
USA) and 99 g of water.
[0655] 10 ml of oral suspension correspond to a single dose of 100
mg of the compound of the invention.
Production:
[0656] The Rhodigel is suspended in ethanol, and the compound of
the invention is added to the suspension. The water is added while
stirring. The mixture is stirred for about 6 h until the swelling
of the Rhodigel is complete.
Solution which can be Administered Orally:
Composition:
[0657] 500 mg of the compound of the invention, 2.5 g of
polysorbate and 97 g of polyethylene glycol 400.20 g of oral
solution correspond to a single dose of 100 mg of the compound
according to the invention.
Production:
[0658] The compound of the invention is suspended in the mixture of
polyethylene glycol and polysorbate with stirring. The stirring
process is continued until the compound according to the invention
has completely dissolved.
i.v. Solution:
[0659] The compound of the invention is dissolved in a
concentration below the saturation solubility in a physiologically
tolerated solvent (e.g. isotonic saline solution, 5% glucose
solution and/or 30% PEG 400 solution). The solution is sterilized
by filtration and used to fill sterile and pyrogen-free injection
containers.
* * * * *